9 results on '"Pijut, Sonja S."'
Search Results
2. Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes
- Author
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Rotroff, Daniel M., Pijut, Sonja S., Skylar W., Jack, John R., Havener, Tammy M., Pujol Onofre, Aurora, Schlüter, Agatha, Graf, Gregory A., Ginsberg, Henry N., Shah, Hetal S., Gao, He, Morieri, Mario-Luca, Doria, Alessandro, Mychaleckyi, Josyf C., Mcleod, Howard L., Buse, John B., Wagner, Michael J., Motsinger-Reif, Alison A., and ACCORD/ACCORDion Investigators
- Subjects
0301 basic medicine ,False discovery rate ,Male ,medicine.medical_specialty ,Genome-wide association study ,Type 2 diabetes ,Disease ,030204 cardiovascular system & hematology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fenofibrate ,Aldehyde Reductase ,Internal medicine ,Diabetes mellitus ,Gene expression ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Pharmacology (medical) ,Smad3 Protein ,Hypolipidemic Agents ,Dyslipidemias ,Pharmacology ,Female ,Gene Expression Profiling ,Genome-Wide Association Study ,Middle Aged ,Pharmacogenomic Testing ,Signal Transduction ,beta Karyopherins ,Diabetes Mellitus, Type 2 ,Lipid Metabolism ,Diabetis ,business.industry ,Diabetes ,nutritional and metabolic diseases ,medicine.disease ,030104 developmental biology ,Endocrinology ,business ,Dyslipidemia ,Type 2 ,medicine.drug - Abstract
Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10(−6)). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D.
- Published
- 2018
3. Factors Regulating Features of Metabolic Syndrome
- Author
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Pijut, Sonja S.
- Subjects
Endocrinology, Diabetes, and Metabolism ,Medical Molecular Biology - Abstract
The collective presence of central obesity, low HDL-cholesterol, and elevated triglycerides, blood pressure, and fasting blood glucose constitutes Metabolic Syndrome (MetS), a disease state that increases the risk of cardiovascular disease (CVD) and Type 2 Diabetes Mellitus (T2DM). Nonalcoholic fatty liver disease (NAFLD), present in up to 90% of obese adults, is also linked to MetS. As in CVD, disruptions in cholesterol metabolism play a contributing role in the development of T2DM and NAFLD. Genes involved in cholesterol synthesis, secretion, and catabolism are diurnally regulated in the liver and adipose. Disruptions in the sleep-wake cycle are thought to potentiate metabolic disorders associated with CVD, thus revealing a potential role of disrupted circadian rhythms in the development of MetS phenotypes. We initially observed that a group of clock-controlled genes in the Par bZip family were downregulated in adipose tissue of obese mice and humans. Further studies revealed that deletion of the core clock gene, Bmal1, from adipose tissue alone (ABKO mice) or in combination with the liver (LABKO mice) altered feeding behavior and locomotor activity. Obesity was increased in LABKO mice but there were no further detrimental effects in either ABKO or LABKO mice. Interestingly, high-fat diet suppressed Bmal1 transcript levels in adipose tissue suggesting that the muted effects observed with genetic Bmal1 deletion were likely due to the overpowering effects of a high-fat diet. Cholesterol metabolizing and bile acid synthesizing enzymes oscillate diurnally at the transcriptional level. Promoting cholesterol elimination through bile acid synthesis and biliary secretion is essential for reducing hepatic cholesterol, a perpetrating factor in the progression of NAFLD. Previous studies in animal models demonstrated that deletion of the hepatic cholesterol transporters, Abcg5 and Abcg8 (G5G8), decreased biliary cholesterol secretion and increased obesity and hepatic steatosis. Ursodiol (Urso) increased G5G8 protein expression and in combination with ezetimibe, a cholesterol-lowering agent, showed promise as a therapeutic for NAFLD. However, bile acid synthesis was suppressed in the presence of Urso and ezetimibe, suggesting that the overall effect on cholesterol elimination was minimized. The increase in G5G8 and decrease in bile acid synthesis was associated with an increase in Fgf15/19, a suppressor of bile acid synthesis. In order to determine if and how FGF15/19 regulates G5G8, mice were injected with FGF19. G5G8 protein expression and biliary total cholesterol were increased. Additionally, G5G8 localized to the canalicular surface of hepatocytes. Urso caused a similar localization of G5G8 that appeared to be dependent of the FGF15/19-FGFR4 signaling pathway. Interestingly, G5G8 was not required for maintaining cholesterol homeostasis in the presence of FGF15/19. Data from murine models suggest Urso and ezetimibe promote cholesterol elimination, though the effects may be limited by the suppression of bile acid synthesis. Nonetheless, there may be a therapeutic window in which optimal cholesterol elimination can be reached. Additionally, the effects of Urso and ezetimibe are variable between mice and humans. Given the clinical availability of the two drugs, the translatability into humans and the potential to address whether Urso and ezetimibe can minimize NAFLD is great.
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- 2017
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4. Effect of peripheral circadian dysfunction on metabolic disease in response to a diabetogenic diet
- Author
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Pijut, Sonja S., primary, Corbett, Danielle E., additional, Wang, Yuhuan, additional, Li, Jianing, additional, Charnigo, Richard J., additional, and Graf, Gregory A., additional
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- 2016
- Full Text
- View/download PDF
5. Genetic Variants in <italic>HSD17B3</italic>, <italic>SMAD3</italic>, and <italic>IPO11</italic> Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.
- Author
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Rotroff, Daniel M., Pijut, Sonja S., Marvel, Skylar W., Jack, John R., Havener, Tammy M., Pujol, Aurora, Schluter, Agatha, Graf, Gregory A., Ginsberg, Henry N., Shah, Hetal S., Gao, He, Morieri, Mario‐Luca, Doria, Alessandro, Mychaleckyi, Josyf C., McLeod, Howard L., Buse, John B., Wagner, Michael J., Motsinger‐Reif, Alison A., and the ACCORD/ACCORDion Investigators
- Subjects
HUMAN genetic variation ,LIPIDS ,TYPE 2 diabetes ,FENOFIBRATE ,CARDIOVASCULAR diseases risk factors ,GENOMICS ,GENE expression ,LABORATORY mice - Abstract
Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in
SMAD3 andIPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10‐6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach.AKR7A3 andHSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions inHsd17b13 gene expression (q < 0.1). Associations of variants inSMAD3 ,IPO11 , andHSD17B13 , with gene expression changes in mice indicate that transforming growth factor‐beta (TGF‐β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
6. The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination
- Author
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Wang, Yuhuan, primary, Liu, Xiaoxi, additional, Pijut, Sonja S., additional, Li, Jianing, additional, Horn, Jamie, additional, Bradford, Emily M., additional, Leggas, Markos, additional, Barrett, Terrence A., additional, and Graf, Gregory A., additional
- Published
- 2015
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- View/download PDF
7. ABCD2 identifies a subclass of peroxisomes in mouse adipose tissue
- Author
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Liu, Xiaoxi, primary, Liu, Jingjing, additional, Lester, Joshua D., additional, Pijut, Sonja S., additional, and Graf, Gregory A., additional
- Published
- 2015
- Full Text
- View/download PDF
8. Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.
- Author
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Rotroff DM, Pijut SS, Marvel SW, Jack JR, Havener TM, Pujol A, Schluter A, Graf GA, Ginsberg HN, Shah HS, Gao H, Morieri ML, Doria A, Mychaleckyi JC, McLeod HL, Buse JB, Wagner MJ, and Motsinger-Reif AA
- Subjects
- Animals, Female, Gene Expression Profiling methods, Genome-Wide Association Study, Humans, Hypolipidemic Agents administration & dosage, Hypolipidemic Agents pharmacokinetics, Male, Mice, Middle Aged, Pharmacogenomic Testing methods, Signal Transduction drug effects, Aldehyde Reductase genetics, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Dyslipidemias blood, Dyslipidemias complications, Dyslipidemias drug therapy, Dyslipidemias genetics, Fenofibrate administration & dosage, Fenofibrate pharmacokinetics, Lipid Metabolism drug effects, Lipid Metabolism genetics, Smad3 Protein genetics, beta Karyopherins genetics
- Abstract
Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10
-6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2018
- Full Text
- View/download PDF
9. Effect of peripheral circadian dysfunction on metabolic disease in response to a diabetogenic diet.
- Author
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Pijut SS, Corbett DE, Wang Y, Li J, Charnigo RJ, and Graf GA
- Subjects
- Animals, Circadian Rhythm, Diabetes Mellitus, Experimental etiology, Diabetes Mellitus, Experimental metabolism, Diet adverse effects, Female, Male, Metabolic Diseases etiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, ARNTL Transcription Factors metabolism, Adipose Tissue metabolism, Chronobiology Disorders etiology, Chronobiology Disorders metabolism, Liver metabolism, Metabolic Diseases metabolism
- Abstract
BMAL1 is a core component of the transcription/translation machinery that regulates central and peripheral circadian rhythms that coordinate behavior and metabolism, respectively. Our objective was to determine the impact of BMAL1 in adipose alone or in combination with liver on metabolic phenotypes. Control, adipose-Bmal1 knockout (ABKO), and liver- and adipose-Bmal1 knockout (LABKO) female mice were placed in TSE System metabolic chambers for metabolic phenotyping. A second cohort of male mice was fed a control or diabetogenic diet, and body weight and composition, glucose tolerance, insulin sensitivity, and serum and hepatic lipids were measured. Both female ABKO and LABKO mice exhibited increased food consumption compared with control mice. ABKO mice also exhibited increased overall activity predominantly during the light phase compared with both control and LABKO mice and were protected from increased weight gain. When the male cohort was challenged with a diabetogenic diet, LABKO mice had increased body weight due to increased fat mass compared with control and ABKO mice. However, these mice did not present further impairments in glycemic control, adipose inflammation, or liver injury. LABKO mice had increased hepatic cholesterol and elevated expression of cholesterol synthesis and uptake genes. Our data indicate that deletion of this allele in adipose or in combination with liver alters feeding behavior and locomotor activity. However, obesity is exacerbated only with the combination of liver and adipose deletion., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
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