115 results on '"SLC13A5"'
Search Results
2. Novel Approaches to Studying SLC13A5 Disease.
- Author
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Beltran, Adriana S.
- Subjects
INDUCED pluripotent stem cells ,TECHNOLOGICAL innovations ,HUMAN physiology - Abstract
The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the intricacy and complexity of the latent human physiology, which is poorly captured by existing animal models. This review explores innovative technologies aimed at bridging such a knowledge gap. First, I provide an overview of SLC13A5 variants in the context of human disease and the specific cell types where the expression of the transporter has been observed. Next, I discuss current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids. Finally, I explore the relevance of these cellular models as platforms for delving into the intricate molecular and cellular mechanisms underlying SLC13A5-related disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. SOFT syndrome with kohlschutter–Tonz syndrome.
- Author
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Mondkar, S, Khadilkar, V, Kasegaonkar, P, and Khadilkar, A
- Subjects
- *
NEUROLOGIC examination , *MARRIAGE , *ATAXIA , *SKELETAL muscle , *HUMAN abnormalities , *FETAL growth retardation , *CONSANGUINITY , *PATENT ductus arteriosus , *NEURODEGENERATION , *PERINATAL death , *MUSCULOSKELETAL system abnormalities , *STATURE , *MUSCLE tone , *DEVELOPMENTAL disabilities , *GENE expression , *DWARFISM , *SEIZURES (Medicine) , *CRANIOSYNOSTOSES , *GROWTH disorders , *CRANIOFACIAL abnormalities , *GENETIC mutation , *ECHOCARDIOGRAPHY , *CHILDREN - Abstract
We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development
- Author
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Dipender Gill, Loukas Zagkos, Rubinder Gill, Thomas Benzing, Jens Jordan, Andreas L. Birkenfeld, Stephen Burgess, and Grit Zahn
- Subjects
SLC13A5 ,Citrate ,Kidney ,Renal function ,Mendelian randomization ,Drug development ,Medicine - Abstract
Abstract Background Solute carrier family 13 member 5 (SLC13A5) is a Na+-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts. Methods The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals. Results We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10−4). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10−13) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns. Conclusions This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function.
- Published
- 2023
- Full Text
- View/download PDF
5. The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development.
- Author
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Gill, Dipender, Zagkos, Loukas, Gill, Rubinder, Benzing, Thomas, Jordan, Jens, Birkenfeld, Andreas L., Burgess, Stephen, and Zahn, Grit
- Subjects
- *
KIDNEY diseases , *DRUG development , *CREATININE , *CITRATES , *DISEASE risk factors , *BLOOD urea nitrogen - Abstract
Background: Solute carrier family 13 member 5 (SLC13A5) is a Na+-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts. Methods: The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals. Results: We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10−4). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10−13) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns. Conclusions: This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Targeting Longevity Gene SLC13A5 : A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis.
- Author
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Zahn, Grit, Baukmann, Hannes A., Wu, Jasmine, Jordan, Jens, Birkenfeld, Andreas L., Dirckx, Naomi, and Schmidt, Marco F.
- Subjects
KREBS cycle ,GENE targeting ,OSTEOPOROSIS ,LONGEVITY ,MEMBRANE transport proteins ,KNOCKOUT mice - Abstract
Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1–5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts' specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5
cKO ) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
7. NaCT/SLC13A5 facilitates citrate import and metabolism under nutrient-limited conditions
- Author
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Kumar, Avi, Cordes, Thekla, Thalacker-Mercer, Anna E, Pajor, Ana M, Murphy, Anne N, and Metallo, Christian M
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Nutrition ,Liver Disease ,Digestive Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Acetyl Coenzyme A ,Adult ,Animals ,Carcinoma ,Hepatocellular ,Cell Hypoxia ,Cell Line ,Tumor ,Cell Survival ,Citrates ,Female ,Gene Editing ,Glutamine ,Humans ,Lipogenesis ,Liver Neoplasms ,Male ,Neurons ,Nutrients ,Rats ,Symporters ,Zinc ,NaCT ,SLC13A5 ,citrate ,hepatocellular carcinoma ,lipogenesis ,neurons ,zinc ,Biochemistry and Cell Biology ,Medical Physiology - Abstract
Citrate lies at a critical node of metabolism, linking tricarboxylic acid metabolism and lipogenesis via acetyl-coenzyme A. Recent studies have observed that deficiency of the sodium-dependent citrate transporter (NaCT), encoded by SLC13A5, dysregulates hepatic metabolism and drives pediatric epilepsy. To examine how NaCT contributes to citrate metabolism in cells relevant to the pathophysiology of these diseases, we apply 13C isotope tracing to SLC13A5-deficient hepatocellular carcinoma (HCC) cells and primary rat cortical neurons. Exogenous citrate appreciably contributes to intermediary metabolism only under hypoxic conditions. In the absence of glutamine, citrate supplementation increases de novo lipogenesis and growth of HCC cells. Knockout of SLC13A5 in Huh7 cells compromises citrate uptake and catabolism. Citrate supplementation rescues Huh7 cell viability in response to glutamine deprivation or Zn2+ treatment, and NaCT deficiency mitigates these effects. Collectively, these findings demonstrate that NaCT-mediated citrate uptake is metabolically important under nutrient-limited conditions and may facilitate resistance to metal toxicity.
- Published
- 2021
8. Novel Approaches to Studying SLC13A5 Disease
- Author
-
Adriana S. Beltran
- Subjects
SLC13A5 ,NaCT ,iPSCs ,neurons ,hepatocytes ,organoids ,Microbiology ,QR1-502 - Abstract
The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the intricacy and complexity of the latent human physiology, which is poorly captured by existing animal models. This review explores innovative technologies aimed at bridging such a knowledge gap. First, I provide an overview of SLC13A5 variants in the context of human disease and the specific cell types where the expression of the transporter has been observed. Next, I discuss current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids. Finally, I explore the relevance of these cellular models as platforms for delving into the intricate molecular and cellular mechanisms underlying SLC13A5-related disorders.
- Published
- 2024
- Full Text
- View/download PDF
9. Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system.
- Author
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Spelbrink, Emily M., Brown, Tanya L., Brimble, Elise, Blanco, Kirsten A., Nye, Kimberly L., and Porter, Brenda E.
- Subjects
MEDICAL records ,RARE diseases ,CITRATES ,GENETIC disorders ,EPILEPTIFORM discharges ,DYSPLASIA ,DEEP brain stimulation ,VOXEL-based morphometry - Abstract
Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation. Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed. Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes. Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
10. Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5.
- Author
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Chen, Fangfang, Willenbockel, Hanna Friederike, and Cordes, Thekla
- Subjects
CITRATES ,HOMEOSTASIS ,MEMBRANE transport proteins ,SMALL molecules ,CELL metabolism ,METABOLISM - Abstract
The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the "multiple-hit theory" and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
11. Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis
- Author
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Grit Zahn, Hannes A. Baukmann, Jasmine Wu, Jens Jordan, Andreas L. Birkenfeld, Naomi Dirckx, and Marco F. Schmidt
- Subjects
mINDY ,SLC13A5 ,citrate ,citrate transporter ,NaCT ,osteoporosis ,Microbiology ,QR1-502 - Abstract
Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1–5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts’ specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.
- Published
- 2023
- Full Text
- View/download PDF
12. Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system
- Author
-
Emily M. Spelbrink, Tanya L. Brown, Elise Brimble, Kirsten A. Blanco, Kimberly L. Nye, and Brenda E. Porter
- Subjects
citrate ,transporter ,epilepsy ,SLC13A5 ,developmental delay ,NACT ,Genetics ,QH426-470 - Abstract
Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation.Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed.Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes.Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders.
- Published
- 2023
- Full Text
- View/download PDF
13. A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth.
- Author
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Dirckx, Naomi, Qian Zhang, Chu, Emily Y., Tower, Robert J., Zhu Li, Shenghao Guo, Shichen Yuan, Khare, Pratik A., Cissy Zhang, Verardo, Angela, Alejandro, Lucy O., Park, Angelina, Faugere, Marie-Claude, Helfand, Stephen L., Somerman, Martha J., Riddle, Ryan C., de Cabo, Rafael, Anne Le, Schmidt-Rohr, Klaus, and Clemens, Thomas L.
- Subjects
- *
CITRATES , *KREBS cycle , *ZINC transporters , *CARRIER proteins , *DENTAL enamel - Abstract
Citrate is a critical metabolic substrate and key regulator of energy metabolism in mammalian cells. It has been known for decades that the skeleton contains most (>85%) of the body’s citrate, but the question of why and how this metabolite should be partitioned in bone has received singularly little attention. Here, we show that osteoblasts use a specialized metabolic pathway to regulate uptake, endogenous production, and the deposition of citrate into bone. Osteoblasts express high levels of the membranous Na+-dependent citrate transporter solute carrier family 13 member 5 (Slc13a5) gene. Inhibition or genetic disruption of Slc13a5 reduced osteogenic citrate uptake and disrupted mineral nodule formation. Bones from mice lacking Slc13a5 globally, or selectively in osteoblasts, showed equivalent reductions in cortical thickness, with similarly compromised mechanical strength. Surprisingly, citrate content in mineral from Slc13a52/2 osteoblasts was increased fourfold relative to controls, suggesting the engagement of compensatory mechanisms to augment endogenous citrate production. Indeed, through the coordinated functioning of the apical membrane citrate transporter SLC13A5 and a mitochondrial zinc transporter protein (ZIP1; encoded by Slc39a1), a mediator of citrate efflux from the tricarboxylic acid cycle, SLC13A5 mediates citrate entry from blood and its activity exerts homeostatic control of cytoplasmic citrate. Intriguingly, Slc13a5-deficient mice also exhibited defective tooth enamel and dentin formation, a clinical feature, which we show is recapitulated in primary teeth from children with SLC13A5 mutations. Together, our results reveal the components of an osteoblast metabolic pathway, which affects bone strength by regulating citrate deposition into mineral hydroxyapatite. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
14. SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy.
- Author
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Goodspeed, Kimberly, Liu, Judy S., Nye, Kimberly L., Prasad, Suyash, Sadhu, Chanchal, Tavakkoli, Fatemeh, Bilder, Deborah A., Minassian, Berge A., and Bailey, Rachel M.
- Subjects
- *
GENE therapy , *GENETICS , *CHILDREN with developmental disabilities , *GENETIC variation , *MEDICAL research , *DEVELOPMENTAL delay , *GENETIC transformation - Abstract
Epileptic encephalopathies may arise from single gene variants. In recent years, next-generation sequencing technologies have enabled an explosion of gene identification in monogenic epilepsies. One such example is the epileptic encephalopathy SLC13A5 deficiency disorder, which is caused by loss of function pathogenic variants to the gene SLC13A5 that results in deficiency of the sodium/citrate cotransporter. Patients typically experience seizure onset within the first week of life and have developmental delay and intellectual disability. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and non-epileptic features of SLC13A5 deficiency disorder. Gene therapy may offer hope to these patients and better clinical outcomes than current available treatments. Here, we discuss SLC13A5 genetics, natural history, available treatments, potential outcomes and assessments, and considerations for translational medical research for an AAV9-based gene replacement therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
15. A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity.
- Author
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Zahn, Grit, Willmes, Diana M., El-Agroudy, Nermeen N., Yarnold, Christopher, Jarjes-Pike, Richard, Schaertl, Sabine, Schreiter, Kay, Gehrmann, Wiebke, Wong, Andrea Kuan Cie, Zordan, Tommaso, König, Jörg, Jordan, Jens, and Birkenfeld, Andreas L.
- Subjects
FATTY liver ,CITRATES ,SMALL molecules ,BODY composition ,ADIPOSE tissues ,OBESITY ,FAT ,INSULIN - Abstract
Mammalian INDY (mINDY, NaCT, gene symbol SLC13A5) is a potential target for the treatment of metabolically associated fatty liver disease (MAFLD). This study evaluated the effects of a selective, cross-species active, non-competitive, non-substrate-like inhibitor of NaCT. First, the small molecule inhibitor ETG-5773 was evaluated for citrate and succinate uptake and fatty acid synthesis in cell lines expressing both human NaCT and mouse Nact. Once its suitability was established, the inhibitor was evaluated in a diet-induced obesity (DIO) mouse model. DIO mice treated with 15 mg/kg compound ETG-5773 twice daily for 28 days had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Liver triglycerides were significantly reduced, and body composition was improved by reducing fat mass, supported by a significant reduction in the expression of genes for lipogenesis such as SREBF1 and SCD1. Most of these effects were also evident after a seven-day treatment with the same dose. Further mechanistic investigation in the seven-day study showed increased plasma β-hydroxybutyrate and activated hepatic adenosine monophosphate-activated protein kinase (AMPK), reflecting findings from Indy (−/−) knockout mice. These results suggest that the inhibitor ETG-5773 blocked citrate uptake mediated by mouse and human NaCT to reduce liver steatosis and body fat and improve glucose regulation, proving the concept of NaCT inhibition as a future liver treatment for MAFLD. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
16. The growing research toolbox for SLC13A5 citrate transporter disorder: a rare disease with animal models, cell lines, an ongoing Natural History Study and an engaged patient advocacy organization.
- Author
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Brown TL, Bainbridge MN, Zahn G, Nye KL, and Porter BE
- Abstract
TESS Research Foundation (TESS) is a patient-led nonprofit organization seeking to understand the basic biology and clinical impact of pathogenic variants in the SLC13A5 gene. TESS aims to improve the fundamental understanding of citrate's role in the brain, and ultimately identify treatments and cures for the associated disease. TESS identifies, organizes, and develops collaboration between researchers, patients, clinicians, and the pharmaceutical industry to improve the lives of those suffering from SLC13A5 citrate transport disorder. TESS and its partners have developed multiple molecular tools, cellular and animal models, and taken the first steps toward drug discovery and development for this disease. However, much remains to be done to improve our understanding of the disorder associated with SLC13A5 variants and identify effective treatments for this devastating disease. Here, we describe the available SLC13A5 resources from the community of experts, to foundational tools, to in vivo and in vitro tools, and discuss unanswered research questions needed to move closer to a cure., Competing Interests: TLB is employed by TESS Research Foundation. MAB, GZ, and BEP are advisors to TESS Research Foundation. KLN is volunteer Executive Director and Founder of TESS Research Foundation. GZ is a minor shareholder and employee of Eternygen GmbH., (© The Author(s), 2024.)
- Published
- 2024
- Full Text
- View/download PDF
17. Gene Therapy: Novel Approaches to Targeting Monogenic Epilepsies.
- Author
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Goodspeed, Kimberly, Bailey, Rachel M., Prasad, Suyash, Sadhu, Chanchal, Cardenas, Jessica A., Holmay, Mary, Bilder, Deborah A., and Minassian, Berge A.
- Subjects
GENE therapy ,EPILEPSY ,DEVELOPMENTAL disabilities ,PEOPLE with epilepsy ,DISABILITIES ,PREMATURE menopause - Abstract
Genetic epilepsies are a spectrum of disorders characterized by spontaneous and recurrent seizures that can arise from an array of inherited or de novo genetic variants and disrupt normal brain development or neuronal connectivity and function. Genetically determined epilepsies, many of which are due to monogenic pathogenic variants, can result in early mortality and may present in isolation or be accompanied by neurodevelopmental disability. Despite the availability of more than 20 antiseizure medications, many patients with epilepsy fail to achieve seizure control with current therapies. Patients with refractory epilepsy—particularly of childhood onset—experience increased risk for severe disability and premature death. Further, available medications inadequately address the comorbid developmental disability. The advent of next-generation gene sequencing has uncovered genetic etiologies and revolutionized diagnostic practices for many epilepsies. Advances in the field of gene therapy also present the opportunity to address the underlying mechanism of monogenic epilepsies, many of which have only recently been described due to advances in precision medicine and biology. To bring precision medicine and genetic therapies closer to clinical applications, experimental animal models are needed that replicate human disease and reflect the complexities of these disorders. Additionally, identifying and characterizing clinical phenotypes, natural disease course, and meaningful outcome measures from epileptic and neurodevelopmental perspectives are necessary to evaluate therapies in clinical studies. Here, we discuss the range of genetically determined epilepsies, the existing challenges to effective clinical management, and the potential role gene therapy may play in transforming treatment options available for these conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
18. Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis.
- Author
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Milosavljevic, Sofia, Glinton, Kevin E., Li, Xiqi, Medeiros, Cláudia, Gillespie, Patrick, Seavitt, John R., Graham, Brett H., and Elsea, Sarah H.
- Subjects
METABOLOMICS ,BILE acids ,LIPID synthesis ,HOMEOSTASIS ,FATTY acids ,LIPID metabolism ,LIVER - Abstract
Though biallelic variants in SLC13A5 are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs of these perturbations are inconsistent across SLC13A5 deficiency patients. To investigate SLC13A5-related disorders, we performed untargeted metabolic analyses on the liver, brain, and serum from a Slc13a5-deficient mouse model. Metabolomic data were analyzed using the connect-the-dots (CTD) methodology and were compared to plasma and CSF metabolomics from SLC13A5-deficient patients. Mice homozygous for the Slc13a5
tm1b/tm1b null allele had perturbations in fatty acids, bile acids, and energy metabolites in all tissues examined. Further analyses demonstrated that for several of these molecules, the ratio of their relative tissue concentrations differed widely in the knockout mouse, suggesting that deficiency of Slc13a5 impacts the biosynthesis and flux of metabolites between tissues. Similar findings were observed in patient biofluids, indicating altered transport and/or flux of molecules involved in energy, fatty acid, nucleotide, and bile acid metabolism. Deficiency of SLC13A5 likely causes a broader state of metabolic dysregulation than previously recognized, particularly regarding lipid synthesis, storage, and metabolism, supporting SLC13A5 deficiency as a lipid disorder. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
19. Gene Therapy: Novel Approaches to Targeting Monogenic Epilepsies
- Author
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Kimberly Goodspeed, Rachel M. Bailey, Suyash Prasad, Chanchal Sadhu, Jessica A. Cardenas, Mary Holmay, Deborah A. Bilder, and Berge A. Minassian
- Subjects
genetic epilepsy ,AAV9 ,Lafora ,SLC13A5 ,SLC6A1 ,gene therapy (GT) ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Genetic epilepsies are a spectrum of disorders characterized by spontaneous and recurrent seizures that can arise from an array of inherited or de novo genetic variants and disrupt normal brain development or neuronal connectivity and function. Genetically determined epilepsies, many of which are due to monogenic pathogenic variants, can result in early mortality and may present in isolation or be accompanied by neurodevelopmental disability. Despite the availability of more than 20 antiseizure medications, many patients with epilepsy fail to achieve seizure control with current therapies. Patients with refractory epilepsy—particularly of childhood onset—experience increased risk for severe disability and premature death. Further, available medications inadequately address the comorbid developmental disability. The advent of next-generation gene sequencing has uncovered genetic etiologies and revolutionized diagnostic practices for many epilepsies. Advances in the field of gene therapy also present the opportunity to address the underlying mechanism of monogenic epilepsies, many of which have only recently been described due to advances in precision medicine and biology. To bring precision medicine and genetic therapies closer to clinical applications, experimental animal models are needed that replicate human disease and reflect the complexities of these disorders. Additionally, identifying and characterizing clinical phenotypes, natural disease course, and meaningful outcome measures from epileptic and neurodevelopmental perspectives are necessary to evaluate therapies in clinical studies. Here, we discuss the range of genetically determined epilepsies, the existing challenges to effective clinical management, and the potential role gene therapy may play in transforming treatment options available for these conditions.
- Published
- 2022
- Full Text
- View/download PDF
20. Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5
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Fangfang Chen, Hanna Friederike Willenbockel, and Thekla Cordes
- Subjects
SLC13A5 ,NaCT ,citrate metabolism ,metabolic niche ,tracing ,mass spectrometry ,Microbiology ,QR1-502 - Abstract
The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the “multiple-hit theory” and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders.
- Published
- 2023
- Full Text
- View/download PDF
21. INDY as a Therapeutic Target for Cardio-Metabolic Disease.
- Author
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Pesta, Dominik and Jordan, Jens
- Subjects
SYMPATHETIC nervous system ,BODY composition ,METABOLIC disorders ,MEMBRANE transport proteins ,INSULIN sensitivity - Abstract
Decreased expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing citrate import into hepatocytes by different strategies can reduce hepatic triglyceride accumulation and improve hepatic insulin sensitivity, even in the absence of effects on body composition. These beneficial effects likely derive from decreased hepatic de novo fatty acid biosynthesis as a result of reduced cytoplasmic citrate levels. While in vivo and in vitro studies show that inhibition of INDY prevents intracellular lipid accumulation, body weight is not affected by organ-specific INDY inhibition. Besides these beneficial metabolic effects, INDY inhibition may also improve blood pressure control through sympathetic nervous system inhibition, partly via reduced peripheral catecholamine synthesis. These effects make INDY a promising candidate with bidirectional benefits for improving both metabolic disease and blood pressure control. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
22. INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans
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Dushyant Mishra, Kavitha Kannan, Kali Meadows, Jacob Macro, Michael Li, Stewart Frankel, and Blanka Rogina
- Subjects
Indy ,SLC13A5 ,citrate transporter ,aging ,longevity gene ,calorie restriction ,Geriatrics ,RC952-954.6 - Abstract
I’m Not Dead Yet (Indy) is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity, and disease. Reduction of Indy gene activity in flies, and its homologs in worms, modulates metabolism and extends longevity. The metabolic changes are similar to what is obtained with caloric restriction (dietary restriction). Similar effects on metabolism have been observed in mice and rats. As a citrate transporter, INDY regulates cytoplasmic citrate levels. Indy flies heterozygous for a P-element insertion have increased spontaneous physical activity, increased fecundity, reduced insulin signaling, increased mitochondrial biogenesis, preserved intestinal stem cell homeostasis, lower lipid levels, and increased stress resistance. Mammalian Indy knockout (mIndy-KO) mice have higher sensitivity to insulin signaling, lower blood pressure and heart rate, preserved memory and are protected from the negative effects of a high-fat diet and some of the negative effects of aging. Reducing mIndy expression in human hepatocarcinoma cells has recently been shown to inhibit cell proliferation. Reduced Indy expression in the fly intestine affects intestinal stem cell proliferation, and has recently been shown to also inhibit germ cell proliferation in males with delayed sperm maturation and decreased spermatocyte numbers. These results highlight a new connection between energy metabolism and cell proliferation. The overrall picture in a variety of species points to a conserved role of INDY for metabolism and health. This is illustrated by an association of high mIndy gene expression with non-alcoholic fatty liver disease in obese humans. mIndy (mSLC13A5) coding region mutations (e.g., loss-of-function) are also associated with adverse effects in humans, such as autosomal recessive early infantile epileptic encephalopathy and Kohlschütter−Tönz syndrome. The recent findings illustrate the importance of mIndy gene for human health and disease. Furthermore, recent work on small-molecule regulators of INDY highlights the promise of INDY-based treatments for ameliorating disease and promoting healthy aging.
- Published
- 2021
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- View/download PDF
23. A novel homozygous SLC13A5 whole‐gene deletion generated by Alu/Alu‐mediated rearrangement in an Iraqi family with epileptic encephalopathy.
- Author
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Duan, Ruizhi, Saadi, Nebal Waill, Grochowski, Christopher M., Bhadila, Ghalia, Faridoun, Afnan, Mitani, Tadahiro, Du, Haowei, Fatih, Jawid M., Jhangiani, Shalini N., Akdemir, Zeynep C., Gibbs, Richard A., Pehlivan, Davut, Posey, Jennifer E., Marafi, Dana, and Lupski, James R.
- Abstract
Biallelic loss‐of‐function (LoF) of SLC13A5 (solute carrier family 13, member 5) induced deficiency in sodium/citrate transporter (NaCT) causes autosomal recessive developmental epileptic encephalopathy 25 with hypoplastic amelogenesis imperfecta (DEE25; MIM #615905). Many pathogenic SLC13A5 single nucleotide variants (SNVs) and small indels have been described; however, no cases with copy number variants (CNVs) have been sufficiently investigated. We describe a consanguineous Iraqi family harboring an 88.5 kb homozygous deletion including SLC13A5 in Chr17p13.1. The three affected male siblings exhibit neonatal‐onset epilepsy with fever‐sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability (GDD/ID), and other variable neurological findings as shared phenotypical features of DEE25. Two of the three affected subjects exhibit hypoplastic amelogenesis imperfecta (AI), while the proband shows no evidence of dental abnormalities or AI at 2 years of age with apparently unaffected primary dentition. Characterization of the genomic architecture at this locus revealed evidence for genomic instability generated by an Alu/Alu‐mediated rearrangement; confirmed by break‐point junction Sanger sequencing. This multiplex family from a distinct population elucidates the phenotypic consequence of complete LoF of SLC13A5 and illustrates the importance of read‐depth‐based CNV detection in comprehensive exome sequencing analysis to solve cases that otherwise remain molecularly unsolved. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
24. SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy
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Kimberly Goodspeed, Judy S. Liu, Kimberly L. Nye, Suyash Prasad, Chanchal Sadhu, Fatemeh Tavakkoli, Deborah A. Bilder, Berge A. Minassian, and Rachel M. Bailey
- Subjects
epileptic encephalopathy ,SLC13A5 ,sodium/citrate cotransporter ,gene therapy ,AAV9 ,Genetics ,QH426-470 - Abstract
Epileptic encephalopathies may arise from single gene variants. In recent years, next-generation sequencing technologies have enabled an explosion of gene identification in monogenic epilepsies. One such example is the epileptic encephalopathy SLC13A5 deficiency disorder, which is caused by loss of function pathogenic variants to the gene SLC13A5 that results in deficiency of the sodium/citrate cotransporter. Patients typically experience seizure onset within the first week of life and have developmental delay and intellectual disability. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and non-epileptic features of SLC13A5 deficiency disorder. Gene therapy may offer hope to these patients and better clinical outcomes than current available treatments. Here, we discuss SLC13A5 genetics, natural history, available treatments, potential outcomes and assessments, and considerations for translational medical research for an AAV9-based gene replacement therapy.
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- 2022
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25. A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
- Author
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Grit Zahn, Diana M. Willmes, Nermeen N. El-Agroudy, Christopher Yarnold, Richard Jarjes-Pike, Sabine Schaertl, Kay Schreiter, Wiebke Gehrmann, Andrea Kuan Cie Wong, Tommaso Zordan, Jörg König, Jens Jordan, and Andreas L. Birkenfeld
- Subjects
MAFLD ,NASH ,NAFLD ,mINDY ,SLC13A5 ,citrate transporter ,Microbiology ,QR1-502 - Abstract
Mammalian INDY (mINDY, NaCT, gene symbol SLC13A5) is a potential target for the treatment of metabolically associated fatty liver disease (MAFLD). This study evaluated the effects of a selective, cross-species active, non-competitive, non-substrate-like inhibitor of NaCT. First, the small molecule inhibitor ETG-5773 was evaluated for citrate and succinate uptake and fatty acid synthesis in cell lines expressing both human NaCT and mouse Nact. Once its suitability was established, the inhibitor was evaluated in a diet-induced obesity (DIO) mouse model. DIO mice treated with 15 mg/kg compound ETG-5773 twice daily for 28 days had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Liver triglycerides were significantly reduced, and body composition was improved by reducing fat mass, supported by a significant reduction in the expression of genes for lipogenesis such as SREBF1 and SCD1. Most of these effects were also evident after a seven-day treatment with the same dose. Further mechanistic investigation in the seven-day study showed increased plasma β-hydroxybutyrate and activated hepatic adenosine monophosphate-activated protein kinase (AMPK), reflecting findings from Indy (−/−) knockout mice. These results suggest that the inhibitor ETG-5773 blocked citrate uptake mediated by mouse and human NaCT to reduce liver steatosis and body fat and improve glucose regulation, proving the concept of NaCT inhibition as a future liver treatment for MAFLD.
- Published
- 2022
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- View/download PDF
26. Gene Transfer Therapy for Neurodevelopmental Disorders.
- Author
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Ozlu, Can, Bailey, Rachel M., Sinnett, Sarah, and Goodspeed, Kimberly D.
- Abstract
Neurodevelopmental disorders (NDDs) include a broad spectrum of disorders that disrupt normal brain development. Though some NDDs are caused by acquired insults (i.e., toxic or infectious encephalopathy) or may be cryptogenic, many NDDs are caused by variants in a single gene or groups of genes that disrupt neuronal development or function. In this review, we will focus on those NDDs with a genetic etiology. The exact mechanism, timing, and progression of the molecular pathology are seldom well known; however, the abnormalities in development typically manifest in similar patterns such as delays or regression in motor function, social skills, and language or cognitive abilities. Severity of impairment can vary widely. At present, only symptomatic treatments are available to manage seizures and behavioral problems commonly seen in NDDs. In recent years, there has been a rapid expansion of research into gene therapy using adeno-associated viruses (AAVs). Using AAVs as vectors to replace the non- or dysfunctional gene in vivo is a relatively simple model which has created an unprecedented opportunity for the future of NDD treatment. Advances in this field are of paramount importance as NDDs lead to a massive lifelong burden of disease on the affected individuals and families. In this article, we review the unique advantages and challenges of AAV gene therapies. We then look at potential applications of gene therapy for 3 of the more common NDDs (Rett syndrome, fragile X syndrome, and Angelman syndrome), as well as 2 less common NDDs (SLC13A5 deficiency disorder and SLC6A1-related disorder). We will review the available natural history of each disease and current state of preclinical studies including a discussion on the application of AAV gene therapies for each disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
27. Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis
- Author
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Sofia Milosavljevic, Kevin E. Glinton, Xiqi Li, Cláudia Medeiros, Patrick Gillespie, John R. Seavitt, Brett H. Graham, and Sarah H. Elsea
- Subjects
SLC13A5 ,lipid synthesis ,untargeted metabolomics ,SLC13A5 deficiency ,citrate transport ,bile acid metabolism ,Microbiology ,QR1-502 - Abstract
Though biallelic variants in SLC13A5 are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs of these perturbations are inconsistent across SLC13A5 deficiency patients. To investigate SLC13A5-related disorders, we performed untargeted metabolic analyses on the liver, brain, and serum from a Slc13a5-deficient mouse model. Metabolomic data were analyzed using the connect-the-dots (CTD) methodology and were compared to plasma and CSF metabolomics from SLC13A5-deficient patients. Mice homozygous for the Slc13a5tm1b/tm1b null allele had perturbations in fatty acids, bile acids, and energy metabolites in all tissues examined. Further analyses demonstrated that for several of these molecules, the ratio of their relative tissue concentrations differed widely in the knockout mouse, suggesting that deficiency of Slc13a5 impacts the biosynthesis and flux of metabolites between tissues. Similar findings were observed in patient biofluids, indicating altered transport and/or flux of molecules involved in energy, fatty acid, nucleotide, and bile acid metabolism. Deficiency of SLC13A5 likely causes a broader state of metabolic dysregulation than previously recognized, particularly regarding lipid synthesis, storage, and metabolism, supporting SLC13A5 deficiency as a lipid disorder.
- Published
- 2022
- Full Text
- View/download PDF
28. Metformin, valproic acid, and starvation induce seizures in a patient with partial SLC13A5 deficiency: a case of pharmaco-synergistic heterozygosity.
- Author
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Kopel, Jonathan, Grooms, Amy, Ganapathy, Vadivel, and Clothier, Jeffrey
- Published
- 2021
- Full Text
- View/download PDF
29. INDY as a Therapeutic Target for Cardio-Metabolic Disease
- Author
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Dominik Pesta and Jens Jordan
- Subjects
citrate transport ,cardiovascular disease ,metabolic disease ,INDY (I’m Not Dead, Yet) ,SLC13A5 ,diabetes ,Microbiology ,QR1-502 - Abstract
Decreased expression of the plasma membrane citrate transporter INDY (acronym I’m Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing citrate import into hepatocytes by different strategies can reduce hepatic triglyceride accumulation and improve hepatic insulin sensitivity, even in the absence of effects on body composition. These beneficial effects likely derive from decreased hepatic de novo fatty acid biosynthesis as a result of reduced cytoplasmic citrate levels. While in vivo and in vitro studies show that inhibition of INDY prevents intracellular lipid accumulation, body weight is not affected by organ-specific INDY inhibition. Besides these beneficial metabolic effects, INDY inhibition may also improve blood pressure control through sympathetic nervous system inhibition, partly via reduced peripheral catecholamine synthesis. These effects make INDY a promising candidate with bidirectional benefits for improving both metabolic disease and blood pressure control.
- Published
- 2022
- Full Text
- View/download PDF
30. Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes
- Author
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Zhihui Li, Linhao Li, Scott Heyward, Shuaiqian Men, Meishu Xu, Tatsuya Sueyoshi, and Hongbing Wang
- Subjects
phenobarbital ,SLC13A5 ,PXR ,CAR ,Cytology ,QH573-671 - Abstract
Phenobarbital (PB), a widely used antiepileptic drug, is known to upregulate the expression of numerous drug-metabolizing enzymes and transporters in the liver primarily via activation of the constitutive androstane receptor (CAR, NR1I3). The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays an important role in intracellular citrate homeostasis that is associated with a number of metabolic syndromes and neurological disorders. Here, we show that PB markedly elevates the expression of SLC13A5 through a pregnane X receptor (PXR)-dependent but CAR-independent signaling pathway. In human primary hepatocytes, the mRNA and protein expression of SLC13A5 was robustly induced by PB treatment, while genetic knockdown or pharmacological inhibition of PXR significantly attenuated this induction. Utilizing genetically modified HepaRG cells, we found that PB induces SLC13A5 expression in both wild type and CAR-knockout HepaRG cells, whereas such induction was fully abolished in the PXR-knockout HepaRG cells. Mechanistically, we identified and functionally characterized three enhancer modules located upstream from the transcription start site or introns of the SLC13A5 gene that are associated with the regulation of PXR-mediated SLC13A5 induction. Moreover, metformin, a deactivator of PXR, dramatically suppressed PB-mediated induction of hepatic SLC13A5 as well as its activation of the SLC13A5 luciferase reporter activity via PXR. Collectively, these data reveal PB as a potent inducer of SLC13A5 through the activation of PXR but not CAR in human primary hepatocytes.
- Published
- 2021
- Full Text
- View/download PDF
31. The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis
- Author
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Kavitha Kannan and Blanka Rogina
- Subjects
Indy ,SLC13A5 ,aging ,intestinal stem cells ,citrate transporter ,longevity gene ,Microbiology ,QR1-502 - Abstract
I’m Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels.
- Published
- 2021
- Full Text
- View/download PDF
32. Molecular Mechanisms of the SLC13A5 Gene Transcription
- Author
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Zhihui Li and Hongbing Wang
- Subjects
SLC13A5 ,transcriptional regulation ,xenobiotic receptor ,pregnane X receptor ,aryl hydrocarbon receptor ,Microbiology ,QR1-502 - Abstract
Citrate is a crucial energy sensor that plays a central role in cellular metabolic homeostasis. The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter highly expressed in the mammalian liver with relatively low levels in the testis and brain, imports citrate from extracellular spaces into the cells. The perturbation of SLC13A5 expression and/or activity is associated with non-alcoholic fatty liver disease, obesity, insulin resistance, cell proliferation, and early infantile epileptic encephalopathy. SLC13A5 has been proposed as a promising therapeutic target for the treatment of these metabolic disorders. In the liver, the inductive expression of SLC13A5 has been linked to several xenobiotic receptors such as the pregnane X receptor and the aryl hydrocarbon receptor as well as certain hormonal and nutritional stimuli. Nevertheless, in comparison to the heightened interest in understanding the biological function and clinical relevance of SLC13A5, studies focusing on the regulatory mechanisms of SLC13A5 expression are relatively limited. In this review, we discuss the current advances in our understanding of the molecular mechanisms by which the expression of SLC13A5 is regulated. We expect this review will provide greater insights into the regulation of the SLC13A5 gene transcription and the signaling pathways involved therein.
- Published
- 2021
- Full Text
- View/download PDF
33. Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder
- Author
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Tanya L. Brown, Kimberly L. Nye, and Brenda E. Porter
- Subjects
SLC13A5 ,citrate ,NaCT ,transporter ,Microbiology ,QR1-502 - Abstract
We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive dysfunction. Additionally, most patients lack tooth enamel (amelogenesis imperfecta). However, patients have not had their overall health and growth described in detail. Here we characterized the non-neurologic health of 15 patients with medical records uploaded to Ciitizen, a cloud-based patient medical records portal. Ciitizen used a query method for data extraction. Overall, the patients’ records suggested a moderate number of gastrointestinal issues related to feeding, reflux, vomiting and weight gain and a diverse number of respiratory complaints. Other organ systems had single or no abnormal diagnoses, including liver, renal and cardiac. Growth parameters were mostly in the normal range during early life, with a trend toward slower growth in the few adolescent patients with data available. The gastrointestinal and pulmonary issues may at least partially be explained by the severity of the neurologic disorder. More data are needed to clarify if growth is impacted during adolescence and if adult patients develop or are protected from non-neurologic disorders.
- Published
- 2021
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- View/download PDF
34. Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions
- Author
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Valeria Jaramillo-Martinez, Sathish Sivaprakasam, Vadivel Ganapathy, and Ina L. Urbatsch
- Subjects
I’m Not Dead Yet ,caloric restriction ,lifespan ,Drosophila INDY ,mammalian INDY ,SLC13A5 ,Microbiology ,QR1-502 - Abstract
INDY (I’m Not Dead Yet) is a plasma membrane transporter for citrate, first identified in Drosophila. Partial deficiency of INDY extends lifespan in this organism in a manner similar to that of caloric restriction. The mammalian counterpart (NaCT/SLC13A5) also transports citrate. In mice, it is the total, not partial, absence of the transporter that leads to a metabolic phenotype similar to that caloric restriction; however, there is evidence for subtle neurological dysfunction. Loss-of-function mutations in SLC13A5 (solute carrier gene family 13, member A5) occur in humans, causing a recessive disease, with severe clinical symptoms manifested by neonatal seizures and marked disruption in neurological development. Though both Drosophila INDY and mammalian INDY transport citrate, the translocation mechanism differs, the former being a dicarboxylate exchanger for the influx of citrate2− in exchange for other dicarboxylates, and the latter being a Na+-coupled uniporter for citrate2−. Their structures also differ as evident from only ~35% identity in amino acid sequence and from theoretically modeled 3D structures. The varied biological consequences of INDY deficiency across species, with the beneficial effects predominating in lower organisms and detrimental effects overwhelming in higher organisms, are probably reflective of species-specific differences in tissue expression and also in relative contribution of extracellular citrate to metabolic pathways in different tissues
- Published
- 2021
- Full Text
- View/download PDF
35. A fluorescent chemical probe CDy9 selectively stains and enables the isolation of live naïve mouse embryonic stem cells.
- Author
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Cho, Seung-Ju, Kim, Keun-Tae, Kim, Jong-Soo, Kwon, Ok-Seon, Go, Young-Hyun, Kang, Nam-Young, Heo, Haejeong, Kim, Mi-Rang, Han, Dong Wook, Moon, Sung-Hwan, Chang, Young-Tae, and Cha, Hyuk-Jin
- Subjects
- *
FLUORESCENT probes , *EMBRYONIC stem cells , *PLURIPOTENT stem cells , *EPIBLAST , *CHIMERISM - Abstract
Human and mouse embryonic stem cells (ESCs) differ in terms of their pluripotency status, i.e., naïve vs. primed. This affects various biological properties and leads to several technical hurdles for future clinical applications, such as difficulties in chimera formation, single-cell passaging, and gene editing. In terms of generating functional human tissues and organs via mammalian interspecies chimerism, a fluorescent chemical probe that specifically labels naïve ESCs would help to isolate these cells and monitor their conversion. This study demonstrates that the fluorescent chemical probe compound of designation yellow 9 (CDy9) selectively stains naïve, but not primed, mouse ESCs (mESCs). CDy9 entered cells via Slc13a5, a highly expressed membrane transporter in naïve mESCs. Fluorescence-based cell sorting based on CDy9 staining successfully separated naïve mESCs from primed mESCs. Mice generated using CDy9 + cells isolated during the conversion of mouse epiblast stem cells into naïve mESCs exhibited coat color chimerism. Furthermore, CDy9 specifically stained cells in the inner cell mass of mouse embryos. These findings suggest that CDy9 is a useful tool to isolate functional naïve mESCs. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
36. Lessons From an MD PhD - From SLC13A5 to Neurology.
- Author
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Kopel J and Clothier J
- Abstract
The journey towards becoming a physician scientist is a long, arduous, and uncertain journey. Few medical students pursue a career as a physician scientist. Even those that do, the path towards maintaining a robust research career and clinical training can be difficult given the personal and social pressures to focus solely on research or clinical work. Despite the long history of science and medicine, there is question concerning the role that physician scientist in modern medicine. As a recent physician scientist graduate, physician scientists are greatly needed in the medical profession. The ability to overlap science, medicine, and the humanities together is an essential part of the producing a well-rounded and effective physician for a rapidly changing profession and world. Through my journey as a physician scientist in training, the lessons I've learned through my training in both the basic science and clinical portions can be helpful for medical students traversing both sides of the divide., Competing Interests: Conflict of interest The authors have no conflicts of interest to report., (© 2023 Greater Baltimore Medical Center.)
- Published
- 2023
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37. INDY—A New Link to Metabolic Regulation in Animals and Humans
- Author
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Blanka Rogina
- Subjects
mIndy ,SLC13A5 ,aging ,metabolism ,longevity gene ,calorie restriction ,Genetics ,QH426-470 - Abstract
The Indy (I’m Not Dead Yet) gene encodes the fly homolog of the mammalian SLC13A5 citrate transporter. Reduced expression of the Indy gene in flies and worms extends their longevity. INDY is expressed in the plasma membrane of metabolically active tissues. Decreased expression of Indy in worms, flies, mice, and rats alters metabolism in a manner similar to calorie restriction. Reducing INDY activity prevents weight gain in flies, worms, and mice, and counteracts the negative effects of age or a high fat diet on metabolism and insulin sensitivity. The metabolic effects of reducing INDY activity are the result of reduced cytoplasmic citrate. Citrate is a key metabolite and has a central role in energy status of the cell by effecting lipid and carbohydrate metabolism and energy production. Thereby newly described drugs that reduce INDY transporting activity increase insulin sensitivity and reduce hepatic lipid levels via its effect on hepatic citrate uptake. A recent report presented the first direct link between increased hepatic levels of human INDY, insulin resistance, and non-alcoholic fatty liver disease in obese humans. Similarly increased hepatic mIndy levels were observed in non-human primates fed on a high fat diet for 2 years. This effect is mediated via the stimulatory effect of the interleukin-6/Stat3 pathway on mINDY hepatic expression. These findings make INDY a potential and very promising target for the treatment of metabolic disorders in humans.
- Published
- 2017
- Full Text
- View/download PDF
38. Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle.
- Author
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Bainbridge, Matthew N., Cooney, Erin, Miller, Marcus, Kennedy, Adam D., Wulff, Jacob E., Donti, Taraka, Jhangiani, Shalini N., Gibbs, Richard A., Elsea, Sarah H., Porter, Brenda E., and Graham, Brett H.
- Subjects
- *
SODIUM cotransport systems , *PEOPLE with epilepsy , *KREBS cycle , *PSYCHOMOTOR disorders , *MASS spectrometry - Abstract
Objective To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay. Methods Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects. Results Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain. Significance Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
39. INDY-A New Link to Metabolic Regulation in Animals and Humans.
- Author
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Rogina, Blanka
- Subjects
METABOLIC regulation ,PHYSIOLOGICAL control systems ,HOMOLOGY (Biology) ,CELL membranes ,LOW-calorie diet - Abstract
The Indy (I'm Not Dead Yet) gene encodes the fly homolog of the mammalian SLC13A5 citrate transporter. Reduced expression of the Indy gene in flies and worms extends their longevity. INDY is expressed in the plasma membrane of metabolically active tissues. Decreased expression of Indy in worms, flies, mice, and rats alters metabolism in a manner similar to calorie restriction. Reducing INDY activity prevents weight gain in flies, worms, and mice, and counteracts the negative effects of age or a high fat diet on metabolism and insulin sensitivity. The metabolic effects of reducing INDY activity are the result of reduced cytoplasmic citrate. Citrate is a key metabolite and has a central role in energy status of the cell by effecting lipid and carbohydrate metabolism and energy production. Thereby newly described drugs that reduce INDY transporting activity increase insulin sensitivity and reduce hepatic lipid levels via its effect on hepatic citrate uptake. A recent report presented the first direct link between increased hepatic levels of human INDY, insulin resistance, and non-alcoholic fatty liver disease in obese humans. Similarly increased hepatic mIndy levels were observed in non-human primates fed on a high fat diet for 2 years. This effect is mediated via the stimulatory effect of the interleukin-6/Stat3 pathway on mINDY hepatic expression. These findings make INDY a potential and very promising target for the treatment of metabolic disorders in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
40. Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations.
- Author
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Weeke, Lauren C., Brilstra, Eva, Braun, Kees P., Zonneveld-Huijssoon, Evelien, Salomons, Gajja S., Koeleman, Bobby P., van Gassen, Koen L., van Straaten, Henrica L., Craiu, Dana, and de Vries, Linda S.
- Abstract
Introduction Early-onset epileptic encephalopathy caused by biallelic SLC13A5 mutations is characterized by seizure onset in the first days of life, refractory epilepsy and developmental delay. Little detailed information about the brain MRI features is available in these patients. Methods Observational study describing the neuro-imaging findings in eight patients (five families) with mutations in the SLC13A5 gene. Seven infants had an MRI in the neonatal period, two had a follow-up MRI at the age of 6 and 18 months and one only at 13 months. One patient had follow-up MRIs at 11 and 16 months and 3 and 6 years of age, but no neonatal MRI. Results All patients presented with refractory neonatal seizures on the first day of life after an uncomplicated pregnancy and term delivery. Six out of seven infants with a neonatal MRI had a characteristic MRI pattern, with punctate white matter lesions (PWML), which were no longer visible at the age of 6 months, but led to gliotic scarring visible on MRI at the age of 18 months. The same pattern of gliotic scarring was seen on the MRIs of the infant without a neonatal scan. One infant had signal abnormalities in the white matter suspected of PWML on T2WI, but these could not be confirmed on other sequences. Conclusion In infants presenting with therapy resistant seizures in the first days after birth, without a clear history of hypoxic-ischemic encephalopathy, but with PWML on their neonatal MRI, a diagnosis of SCL13A5 related epileptic encephalopathy should be considered. [ABSTRACT FROM AUTHOR]
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- 2017
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41. Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy.
- Author
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Alhakeem, Afnan, Alshibani, Faisal, and Tabarki, Brahim
- Subjects
- *
TREATMENT of epilepsy , *ANTICONVULSANTS , *DRUG resistance , *GENETIC disorders , *STATUS epilepticus - Abstract
Introduction SLC13A5 -related epileptic encephalopathy is a recently described autosomal recessive disorder that is characterized by infantile epilepsy and developmental delay. Seizures are markedly drug resistant and often induced by fever; they mainly occur in clusters, sometimes evolving into status epilepticus. Methods and results We report the use of stiripentol as an adjunctive therapy in three siblings with drug-resistant SLC13A5 -related epilepsy. The three patients showed remarkable improvement in the severity and frequency of seizures, status epilepticus, emergency department visits, and alertness. Conclusion These observations extend the use of stiripentol beyond the classical Dravet syndrome, and further studies on the use of this drug in drug-resistant epilepsy, mainly of genetic origin, are warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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42. Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes
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Tatsuya Sueyoshi, Zhihui Li, Linhao Li, Meishu Xu, Hongbing Wang, Scott Heyward, and Shuaiqian Men
- Subjects
QH301-705.5 ,PXR ,phenobarbital ,Response Elements ,Models, Biological ,Biochemistry ,Article ,Downregulation and upregulation ,Constitutive androstane receptor ,Genetics ,Humans ,RNA, Messenger ,Biology (General) ,Enhancer ,Molecular Biology ,Cells, Cultured ,Constitutive Androstane Receptor ,Pregnane X receptor ,Gene knockdown ,Base Sequence ,Symporters ,Chemistry ,Pregnane X Receptor ,Wild type ,General Medicine ,SLC13A5 ,CAR ,Introns ,Metformin ,Cell biology ,Solute carrier family ,Gene Expression Regulation ,Hepatocytes ,Signal transduction ,Biotechnology - Abstract
Phenobarbital (PB), a widely used antiepileptic drug, is known to upregulate the expression of numerous drug-metabolizing enzymes and transporters in the liver primarily via activation of the constitutive androstane receptor (CAR, NR1I3). The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays an important role in intracellular citrate homeostasis that is associated with a number of metabolic syndromes and neurological disorders. Here, we show that PB markedly elevates the expression of SLC13A5 through a pregnane X receptor (PXR)-dependent but CAR-independent signaling pathway. In human primary hepatocytes, the mRNA and protein expression of SLC13A5 was robustly induced by PB treatment, while genetic knockdown or pharmacological inhibition of PXR significantly attenuated this induction. Utilizing genetically modified HepaRG cells, we found that PB induces SLC13A5 expression in both wild type and CAR-knockout HepaRG cells, whereas such induction was fully abolished in the PXR-knockout HepaRG cells. Mechanistically, we identified and functionally characterized three enhancer modules located upstream from the transcription start site or introns of the SLC13A5 gene that are associated with the regulation of PXR-mediated SLC13A5 induction. Moreover, metformin, a deactivator of PXR, dramatically suppressed PB-mediated induction of hepatic SLC13A5 as well as its activation of the SLC13A5 luciferase reporter activity via PXR. Collectively, these data reveal PB as a potent inducer of SLC13A5 through the activation of PXR but not CAR in human primary hepatocytes.
- Published
- 2021
43. Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder
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Brenda E. Porter, Tanya L. Brown, and Kimberly L. Nye
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Citrate transporter ,Microbiology ,Biochemistry ,Article ,Internal medicine ,Medicine ,Amelogenesis imperfecta ,citrate ,Medical diagnosis ,Molecular Biology ,Adult patients ,business.industry ,Medical record ,medicine.disease ,QR1-502 ,Early life ,transporter ,SLC13A5 ,Vomiting ,medicine.symptom ,NaCT ,business ,Weight gain - Abstract
We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive dysfunction. Additionally, most patients lack tooth enamel (amelogenesis imperfecta). However, patients have not had their overall health and growth described in detail. Here we characterized the non-neurologic health of 15 patients with medical records uploaded to Ciitizen, a cloud-based patient medical records portal. Ciitizen used a query method for data extraction. Overall, the patients’ records suggested a moderate number of gastrointestinal issues related to feeding, reflux, vomiting and weight gain and a diverse number of respiratory complaints. Other organ systems had single or no abnormal diagnoses, including liver, renal and cardiac. Growth parameters were mostly in the normal range during early life, with a trend toward slower growth in the few adolescent patients with data available. The gastrointestinal and pulmonary issues may at least partially be explained by the severity of the neurologic disorder. More data are needed to clarify if growth is impacted during adolescence and if adult patients develop or are protected from non-neurologic disorders.
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- 2021
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44. Molecular Mechanisms of the SLC13A5 Gene Transcription
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Hongbing Wang and Zhihui Li
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Pregnane X receptor ,xenobiotic receptor ,biology ,aryl hydrocarbon receptor ,Endocrinology, Diabetes and Metabolism ,Fatty liver ,Review ,Aryl hydrocarbon receptor ,medicine.disease ,Biochemistry ,Microbiology ,QR1-502 ,Cell biology ,Solute carrier family ,pregnane X receptor ,biology.protein ,Transcriptional regulation ,Extracellular ,medicine ,SLC13A5 ,transcriptional regulation ,Signal transduction ,Receptor ,Molecular Biology - Abstract
Citrate is a crucial energy sensor that plays a central role in cellular metabolic homeostasis. The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter highly expressed in the mammalian liver with relatively low levels in the testis and brain, imports citrate from extracellular spaces into the cells. The perturbation of SLC13A5 expression and/or activity is associated with non-alcoholic fatty liver disease, obesity, insulin resistance, cell proliferation, and early infantile epileptic encephalopathy. SLC13A5 has been proposed as a promising therapeutic target for the treatment of these metabolic disorders. In the liver, the inductive expression of SLC13A5 has been linked to several xenobiotic receptors such as the pregnane X receptor and the aryl hydrocarbon receptor as well as certain hormonal and nutritional stimuli. Nevertheless, in comparison to the heightened interest in understanding the biological function and clinical relevance of SLC13A5, studies focusing on the regulatory mechanisms of SLC13A5 expression are relatively limited. In this review, we discuss the current advances in our understanding of the molecular mechanisms by which the expression of SLC13A5 is regulated. We expect this review will provide greater insights into the regulation of the SLC13A5 gene transcription and the signaling pathways involved therein.
- Published
- 2021
45. Arylhydrocarbon receptor-dependent mIndy (Slc13a5) induction as possible contributor to benzo[a]pyrene-induced lipid accumulation in hepatocytes.
- Author
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Neuschäfer-Rube, Frank, Schraplau, Anne, Schewe, Bettina, Lieske, Stefanie, Krützfeldt, Julia-Mignon, Ringel, Sebastian, Henkel, Janin, Birkenfeld, Andreas L., and Püschel, Gerhard P.
- Subjects
- *
FATTY liver , *ARYL hydrocarbon receptors , *BIOACCUMULATION , *LIVER cells , *TRIGLYCERIDES , *PATIENTS - Abstract
Non-alcoholic fatty liver disease is a growing problem in industrialized and developing countries. Hepatic lipid accumulation is the result of an imbalance between fatty acid uptake, fatty acid de novo synthesis, β-oxidation and secretion of triglyceride-rich lipoproteins from the hepatocyte. A central regulator of hepatic lipid metabolism is cytosolic citrate that can either be derived from the mitochondrium or be taken up from the blood via the plasma membrane sodium citrate transporter NaCT, the product of the mammalian INDY gene (SLC13A5). m INDY ablation protects against diet-induced steatosis whereas m INDY expression is increased in patients with hepatic steatosis. Diet-induced hepatic steatosis is also enhanced by activation of the arylhyrocarbon receptor (AhR) both in humans and animal models. Therefore, the hypothesis was tested whether the m INDY gene might be a target of the AhR. In accordance with such a hypothesis, the AhR activator benzo[a]pyrene induced the m INDY expression in primary cultures of rat hepatocytes in an AhR-dependent manner. This induction resulted in an increased citrate uptake and citrate incorporation into lipids which probably was further enhanced by the benzo[a]pyrene-dependent induction of key enzymes of fatty acid synthesis. A potential AhR binding site was identified in the m INDY promoter that appears to be conserved in the human promoter. Elimination or mutation of this site largely abolished the activation of the m INDY promoter by benzo[a]pyrene. This study thus identified the m INDY as an AhR target gene. AhR-dependent induction of the m INDY gene might contribute to the development of hepatic steatosis. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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46. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia.
- Author
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Hardies, Katia, de Kovel, Carolien G. F., Weckhuysen, Sarah, Asselbergh, Bob, Geuens, Thomas, Deconinck, Tine, Azmi, Abdelkrim, May, Patrick, Brilstra, Eva, Becker, Felicitas, Barisic, Nina, Craiu, Dana, Braun, Kees P. J., Lal, Dennis, Thiele, Holger, Schubert, Julian, Weber, Yvonne, van 't Slot, Ruben, Nürnberg, Peter, and Balling, Rudi
- Abstract
The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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47. The mammalian citrate transporter mINDY (I’m not dead yet) and its protective role in hepatic metabolism
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Daniels, Martin André
- Subjects
Diabetes mellitus ,INDY ,SLC13A5 ,citrate ,knockout mouse ,liver ,metabolism ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,metabolic syndrome - Abstract
The soaring global prevalence of metabolic disease including obesity, type 2 diabetes mellitus and NAFLD warrants the search for novel pharmacological targets. Across species, decreased function of the transmembrane carboxylate transporter mINDY (I’m not dead yet) confers a metabolic phenotype akin to caloric restriction, including protection against diet-induced obesity, insulin resistance, and hepatic steatosis. However, the underlying mechanism is not fully understood. Based on mINDY’s high expression levels in mammalian livers, we examined to what extent liver-specific deletion of mINDY contributes to the protective phenotype observed in the whole-body mINDY knockout (INKO) model. We were the first to establish a liver-specific conditional mINDY knockout (LINKO) mouse. We performed comprehensive metabolic phenotyping, including body composition, glucose disposal, gas exchange and insulin sensitivity over 16 weeks across three dietary regimens of differing caloric density: Normal chow diet (NCD), high-fat diet (HFD) and high-fat diet with sucrose-enriched water (HFD+S). We assessed capacity for glucose production in LINKO primary hepatocytes and screened for gene expression changes in LINKO liver samples. When compared to WT controls, LINKO mice did not show differences in body weight and length, body composition and response to intraperitoneal glucose tolerance tests. In hyperinsulinemic-euglycemic clamps, glucose infusion rates did not differ between the groups; however, we observed suppressed glycolysis and increases in clamp glucose clearance and glycogen synthesis in HFD-fed LINKO mice, relative to WT controls. Respirometry yielded conflicting results, with LINKO mice in the HFD cohort showing slightly increased energy expenditure relative to WT controls, but the opposite effect occurring in the HFD+S-cohort. Respiratory exchange ratio was significantly elevated in HFD-fed LINKO homozygotes compared to WT controls, indicating a shift towards carbohydrate catabolism. LINKO primary hepatocytes showed increased capacity for glucose production compared to WT controls. Lastly, LINKO livers showed increased expression of genes implicated in mitochondrial function and unfolded protein response, but no differences in genes related to lipid or glucose metabolism and inflammation. Our data show that liver-specific deletion of mINDY improved whole body glucose clearance and energy expenditure in HFD-fed mice, but did not reduce body weight. Thus, the LINKO model did not fully replicate the phenotype seen previously in the INKO model. These data suggest that other organs than the liver also contribute to that phenotype; more studies in different organ systems are needed for a comprehensive understanding of mINDY’s role in metabolism and in order to pave the way towards novel treatments of metabolic disease., Die global steigende Prävalenz metabolischer Erkrankungen, darunter das metabolische Syndrom, Diabetes mellitus Typ 2 und die nichtalkoholische Fettleberkrankheit, vermittelt einen Bedarf nach neuen und effektiveren pharmakologischen Ansatzpunkten. In verschiedenen Tiermodellen wurde eine verringerte Funktion des Transmembran-Carboxylat-Transportproteins mINDY (Säugetierhomolog, „I’m not dead yet“) mit einem der kalorischen Restriktion ähnelnden metabolischen Phänotypen assoziiert, charakterisiert durch Schutz gegen diätbedingte Fettleibigkeit, Insulinresistenz und hepatische Steatose. INDYs Substratpräferenz für Citrat sowie die hohe Expressionsdichte in murinen Hepatozyten legen nahe, dass INDY’s Einfluss auf die Energiehomöostase auf einer Schlüsselrolle im Intermediärstoffwechsel beruhen könnte. Wir untersuchten daher, ob die Abwesenheit von mINDY in der Leber einen ähnlich ausgeprägten metabolischen Phänotypen wie das Ganzkörperknockoutmodell erzeugen kann. Erstmals etablierten wir eine leberspezifische konditionelle mINDY Knockout- (LINKO-) Maus und charakterisierten umfassend deren Stoffwechsel. Wir bestimmten Körpermaße und -zusammensetzung, Glukosetoleranz, Gasaustausch sowie Insulinsensitivität über einen 16-wöchigen Zeitraum unter drei Diätinterventionen unterschiedlicher kalorischer Dichte: Normal chow diet (NCD), Hochfettdiät (HFD) und Hochfettdiät mit Sucrose-angereichertem Trinkwasser (HFD+S). Zudem bestimmten wir die Kapazität für glukagonstimulierte Glukoseproduktion in LINKO-Primärhepatozyten und führten ein Screening auf genetische Expressionsänderungen in LINKO-Leberproben durch. LINKO-Mäuse und Wildtyp-Kontrollen unterschieden sich nicht in Körpermaßen, Körperzusammensetzung und Glukosetoleranz. Im hyperinsulinämisch-euglykämischen Clamp zeigte sich kein Unterschied in den Glukoseinfusionsraten; LINKO-Mäuse in der HFD-Kohorte wiesen aber relativ zu Wildtyp-Mäusen eine gesteigerte Glukose-Clearance und Glykogensynthese sowie eine verringerte Glykolyse auf. Respirometrisch zeigte sich ein gesteigerter Energieverbrauch in LINKO-Mäusen auf HFD, aber der gegenteilige Trend in den Mäusen der HFD+S-Kohorte. Das Gasaustauschverhältnis war in LINKO-Mäusen der HFD-Kohorte geringfügig, aber signifikant erhöht, was auf eine erhöhte Neigung zum Katabolismus von Kohlenhydraten hindeutet. LINKO-Primärhepatozyten zeigten im Vergleich mit Wildtyp-Kontrollen eine gesteigerte Kapazität zur Produktion von Glukose unter Stimulation durch Glukagon. Zuletzt wiesen LINKO-Leberproben eine gesteigerte Expression von Genen der mitochondrialen Funktion und ER-Stressantwort auf, jedoch keine Expressionsunterschiede in Genen des Fett-, sowie Glukosestoffwechsels oder der Inflammation. Zusammenfassend zeigten sich im LINKO-Mausmodell zwar leichte metabolische Effekte, diese waren jedoch deutlich schwächer ausgeprägt als die Befunde im mINDY-Ganzkörperknockoutmodell. Da neuere Studien durch interventionelle Methoden der leberspezifischen Inhibition von mINDY jedoch stärkere Phänotypen erzeugen konnten, stellt der Transporter weiterhin einen vielversprechenden pharmakologischen Ansatzpunkt dar. Weitere Studien in verschiedenen Organsystemen sind notwendig, um ein besseres Verständnis der Rolle des Citrat-Transporters im Energiehaushalt zu ermöglichen und einen möglichen neuen therapeutischen Ansatz metabolischer Erkrankungen weiter zu erschließen.
- Published
- 2021
48. NaCT/SLC13A5 facilitates citrate import and metabolism under nutrient-limited conditions
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Anne N. Murphy, Anna E. Thalacker-Mercer, Ana M. Pajor, Thekla Cordes, Christian M. Metallo, and Avi Kumar
- Subjects
Male ,Glutamine ,Medical Physiology ,neurons ,Pharmacology ,Nutrient ,2.1 Biological and endogenous factors ,citrate ,Citrates ,Biology (General) ,Aetiology ,Gene Editing ,Neurons ,Tumor ,Symporters ,Chemistry ,Liver Disease ,zinc ,Liver Neoplasms ,hepatocellular carcinoma ,Cell Hypoxia ,Pathophysiology ,Zinc ,Hepatocellular carcinoma ,Lipogenesis ,SLC13A5 ,Female ,Adult ,Carcinoma, Hepatocellular ,QH301-705.5 ,Cell Survival ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Acetyl Coenzyme A ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lipogenesis ,Nutrition ,Catabolism ,Carcinoma ,Hepatocellular ,Nutrients ,Metabolism ,medicine.disease ,Rats ,Biochemistry and Cell Biology ,NaCT ,Digestive Diseases ,Drug metabolism - Abstract
SUMMARY Citrate lies at a critical node of metabolism, linking tricarboxylic acid metabolism and lipogenesis via acetyl-coenzyme A. Recent studies have observed that deficiency of the sodium-dependent citrate transporter (NaCT), encoded by SLC13A5, dysregulates hepatic metabolism and drives pediatric epilepsy. To examine how NaCT contributes to citrate metabolism in cells relevant to the pathophysiology of these diseases, we apply 13C isotope tracing to SLC13A5-deficient hepatocellular carcinoma (HCC) cells and primary rat cortical neurons. Exogenous citrate appreciably contributes to intermediary metabolism only under hypoxic conditions. In the absence of glutamine, citrate supplementation increases de novo lipogenesis and growth of HCC cells. Knockout of SLC13A5 in Huh7 cells compromises citrate uptake and catabolism. Citrate supplementation rescues Huh7 cell viability in response to glutamine deprivation or Zn2+ treatment, and NaCT deficiency mitigates these effects. Collectively, these findings demonstrate that NaCT-mediated citrate uptake is metabolically important under nutrient-limited conditions and may facilitate resistance to metal toxicity., Graphical abstract, In brief Using isotope tracing, 13C MFA, and proliferation assays, Kumar et al. show that NaCT-mediated extracellular citrate is cytosolically catabolized, contributing to de novo lipogenesis (DNL) in HCC cells. Furthermore, extracellular citrate import by NaCT promotes growth in oxygen- and glutamine-limited conditions and protects against zinc-induced toxicity.
- Published
- 2021
49. A genetic model for the secretory stage of dental enamel formation.
- Author
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Simmer, James P., Hu, Jan C-C., Hu, Yuanyuan, Zhang, Shelly, Liang, Tian, Wang, Shih-Kai, Kim, Jung-Wook, Yamakoshi, Yasuo, Chun, Yong-Hee, Bartlett, John D., and Smith, Charles E.
- Subjects
- *
AMELOBLASTS , *DENTAL enamel , *GENETIC models , *BASAL lamina , *AMELOGENESIS , *DENTIN , *HUMAN genes - Abstract
A Hypothetical Molecular Model Showing How Ameloblasts Make Oriented Enamel Ribbons. [Display omitted] • Forty one genes are known to cause defects during the secretory stage of amelogenesis. • We propose a model for enamel mineral ribbon formation inclusive of these 41 genes. • Enamel ribbon formation is an evolutionary adaptation of the basement membrane. • Integrins α4/ß6; αVß6, COL17A1, Laminin 332, SLC13A5, ACP4, Enamelin, Ameloblastin. The revolution in genetics has rapidly increased our knowledge of human and mouse genes that are critical for the formation of dental enamel and helps us understand how enamel evolved. In this graphical review we focus on the roles of 41 genes that are essential for the secretory stage of amelogenesis when characteristic enamel mineral ribbons initiate on dentin and elongate to expand the enamel layer to the future surface of the tooth. Based upon ultrastructural analyses of genetically modified mice, we propose a molecular model explaining how a cell attachment apparatus including collagen 17, α6ß4 and αvß6 integrins, laminin 332, and secreted enamel proteins could attach to individual enamel mineral ribbons and mold their cross-sectional dimensions as they simultaneously elongate and orient them in the direction of the retrograde movement of the ameloblast membrane. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
50. Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes.
- Author
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Li, Zhihui, Li, Linhao, Heyward, Scott, Men, Shuaiqian, Xu, Meishu, Sueyoshi, Tatsuya, and Wang, Hongbing
- Subjects
- *
PREGNANE X receptor , *LIVER cells , *ANDROSTANE receptors , *PHENOBARBITAL , *GENE enhancers , *LIVER enzymes - Abstract
Phenobarbital (PB), a widely used antiepileptic drug, is known to upregulate the expression of numerous drug-metabolizing enzymes and transporters in the liver primarily via activation of the constitutive androstane receptor (CAR, NR1I3). The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays an important role in intracellular citrate homeostasis that is associated with a number of metabolic syndromes and neurological disorders. Here, we show that PB markedly elevates the expression of SLC13A5 through a pregnane X receptor (PXR)-dependent but CAR-independent signaling pathway. In human primary hepatocytes, the mRNA and protein expression of SLC13A5 was robustly induced by PB treatment, while genetic knockdown or pharmacological inhibition of PXR significantly attenuated this induction. Utilizing genetically modified HepaRG cells, we found that PB induces SLC13A5 expression in both wild type and CAR-knockout HepaRG cells, whereas such induction was fully abolished in the PXR-knockout HepaRG cells. Mechanistically, we identified and functionally characterized three enhancer modules located upstream from the transcription start site or introns of the SLC13A5 gene that are associated with the regulation of PXR-mediated SLC13A5 induction. Moreover, metformin, a deactivator of PXR, dramatically suppressed PB-mediated induction of hepatic SLC13A5 as well as its activation of the SLC13A5 luciferase reporter activity via PXR. Collectively, these data reveal PB as a potent inducer of SLC13A5 through the activation of PXR but not CAR in human primary hepatocytes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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