118 results on '"Marica Meroni"'
Search Results
2. Cardiometabolic risk factors in MASLD patients with HCC: the other side of the coin
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Marica Meroni, Miriam Longo, and Paola Dongiovanni
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MASLD ,HCC ,metabolic dysfunctions ,cholesterol ,carotid plaques ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) constitutes the commonest cause of chronic liver disorder worldwide, whereby affecting around one third of the global population. This clinical condition may evolve into Metabolic Dysfunction-Associated Steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC), in a predisposed subgroup of patients. The complex pathogenesis of MASLD is severely entangled with obesity, dyslipidemia and type 2 diabetes (T2D), so far so nutritional and lifestyle recommendations may be crucial in influencing the risk of HCC and modifying its prognosis. However, the causative association between HCC onset and the presence of metabolic comorbidities is not completely clarified. Therefore, the present review aimed to summarize the main literature findings that correlate the presence of inherited or acquired hyperlipidemia and metabolic risk factors with the increased predisposition towards liver cancer in MASLD patients. Here, we gathered the evidence underlining the relationship between circulating/hepatic lipids, cardiovascular events, metabolic comorbidities and hepatocarcinogenesis. In addition, we reported previous studies supporting the impact of triglyceride and/or cholesterol accumulation in generating aberrancies in the intracellular membranes of organelles, oxidative stress, ATP depletion and hepatocyte degeneration, influencing the risk of HCC and its response to therapeutic approaches. Finally, our pursuit was to emphasize the link between HCC and the presence of cardiometabolic abnormalities in our large cohort of histologically-characterized patients affected by MASLD (n=1538), of whom 86 had MASLD-HCC by including unpublished data.
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- 2024
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3. DGAT1 and DGAT2 Inhibitors for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Management: Benefits for Their Single or Combined Application
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Miriam Longo, Erika Paolini, Pietro Di Benedetto, Elena Tomassini, Marica Meroni, and Paola Dongiovanni
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MASLD ,DGAT ,pharmacological therapy ,MASH ,fibrosis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Inhibiting diacylglycerol acetyltransferase (DGAT1, DGAT2) enzymes (iDGAT1, iDGAT2), involved in triglyceride (TG) synthesis, improves hepatic steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients. However, their potential synergism in disease onset (SLD) and progression (metabolic dysfunction-associated steatohepatitis, fibrosis) has been poorly explored. We investigated iDGAT1 and iDGAT2 efficacy, alone or combined (iDGAT1/2) on fat accumulation and hepatocellular injury in hepatocytes (HepG2) and on fibrogenic processes in hepatic stellate cells (LX2). We further tested whether the addition of MitoQ antioxidant to iDGAT1/2 would enhance their effects. SLD and MASH conditions were reproduced in vitro by supplementing Dulbecco’s Modified Eagle’s Medium (DMEM) with palmitic/oleic acids (PAOA) alone (SLD-medium), or plus Lipopolisaccaride (LPS), fructose, and glucose (MASH-medium). In SLD-medium, iDGAT1 and iDGAT2 individually, and even more in combination, reduced TG synthesis in HepG2 cells. Markers of hepatocellular damage were slightly decreased after single iDGAT exposure. Conversely, iDGAT1/2 counteracted ER/oxidative stress and inflammation and enhanced mitochondrial Tricarboxylic acid cycle (TCA) and respiration. In HepG2 cells under a MASH-like condition, only iDGAT1/2 effectively ameliorated TG content and oxidative and inflammatory mediators, further improving bioenergetic balance. LX2 cells, challenged with SLD/MASH media, showed less proliferation and slower migration rates in response to iDGAT1/2 drugs. MitoQ combined with iDGAT1/2 improved cell viability and dampened free fatty acid release by stimulating β-oxidation. Dual DGAT inhibition combined with antioxidants open new perspectives for MASLD management.
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- 2024
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4. Salivary biomarkers: novel noninvasive tools to diagnose chronic inflammation
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Paola Dongiovanni, Marica Meroni, Sara Casati, Riccardo Goldoni, Douglas Vieira Thomaz, Nermin Seda Kehr, Daniela Galimberti, Massimo Del Fabbro, and Gianluca M. Tartaglia
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Dentistry ,RK1-715 - Abstract
Abstract Several chronic disorders including type 2 diabetes (T2D), obesity, heart disease and cancer are preceded by a state of chronic low-grade inflammation. Biomarkers for the early assessment of chronic disorders encompass acute phase proteins (APP), cytokines and chemokines, pro-inflammatory enzymes, lipids and oxidative stress mediators. These substances enter saliva through the blood flow and, in some cases, there is a close relation between their salivary and serum concentration. Saliva can be easily collected and stored with non-invasive and cost-saving procedures, and it is emerging the concept to use it for the detection of inflammatory biomarkers. To this purpose, the present review aims to discuss the advantages and challenges of using standard and cutting-edge techniques to discover salivary biomarkers which may be used in diagnosis/therapy of several chronic diseases with inflammatory consequences with the pursuit to possibly replace conventional paths with detectable soluble mediators in saliva. Specifically, the review describes the procedures used for saliva collection, the standard approaches for the measurement of salivary biomarkers and the novel methodological strategies such as biosensors to improve the quality of care for chronically affected patients.
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- 2023
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5. Circulating indian hedgehog is a marker of the hepatocyte-TAZ pathway in experimental NASH and is elevated in humans with NASH
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Mary Patricia Moore, Xiaobo Wang, Hongxue Shi, Marica Meroni, Alessandro Cherubini, Luisa Ronzoni, Elizabeth J. Parks, Jamal A. Ibdah, R. Scott Rector, Luca Valenti, Paola Dongiovanni, and Ira Tabas
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NASH ,NAFLD ,Fibrosis ,TAZ ,IHH ,Biomarker ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is emerging as the most common cause of liver disease. For evaluation of therapies, there is a pressing need to identify non-invasive, mechanism-based biomarkers. A pro-fibrotic process relevant to human NASH involves a pathway in which a transcriptional regulator called TAZ (WWTR1) in hepatocytes induces the secretion of pro-fibrotic Indian hedgehog (IHH). We therefore reasoned that circulating IHH may be a useful mechanism-based marker to assess changes in NASH fibrosis. Methods: Circulating IHH was assessed in wild-type and hepatocyte-TAZ-silenced NASH mice and in three separate cohorts of patients with mild–moderate NASH. Results: Circulating IHH was elevated in mice with diet-induced NASH compared with chow-fed mice or with NASH mice in which hepatocyte TAZ was silenced, which is an effective means to decrease NASH fibrosis. In patients with fatty liver disease with or without NASH, NASH fibrosis was associated with increased concentrations of circulating IHH. Conclusions: The results of these analyses support further investigation to determine whether circulating IHH may be useful as a mechanism-based indicator of target engagement in anticipated future clinical trials testing NASH fibrosis therapies that block the IHH pathway. Impact and implications: Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is a common cause of liver disease. Circulating biomarkers that reflect liver fibrosis in NASH would be very useful to evaluate therapies. One mechanism of NASH fibrosis with potential as a therapeutic target involves a liver-secreted protein called Indian hedgehog (IHH). We report that circulating levels of IHH in experimental and human NASH associates with NASH and NASH-associated liver fibrosis, providing the premise for further investigation into using circulating IHH to evaluate anticipated future NASH therapies that block the IHH pathway in liver.
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- 2023
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6. PNPLA3 rs738409 Genetic Variant Inversely Correlates with Platelet Count, Thereby Affecting the Performance of Noninvasive Scores of Hepatic Fibrosis
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Marica Meroni and Paola Dongiovanni
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MASLD ,platelets ,PNPLA3 ,genetics ,diagnostic accuracy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Noninvasive tests (NITs) including platelets (PLTs) have been proposed to replace hepatic biopsy for the diagnosis of nonalcoholic fatty liver disease (NAFLD), or as more recently redefined, metabolic dysfunction-associated steatotic liver disease (MASLD). There has been reported an inverse correlation between PLTs and progressive MASLD, which is also affected by the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C>G mutation. However, the correlation between low PLTs and PNPLA3 genotype has been poorly investigated. We stratified 1155 biopsy-proven MASLD patients according to PNPLA3 genotype. The hepatic expression of genes involved in megakaryopoiesis was investigated in n = 167 bariatric patients by RNAseq. PLT count progressively decreased according to the number of PNPLA3 at-risk alleles, irrespective of the presence of advanced fibrosis. The hepatic expression of genes involved in PLT biogenesis was associated with the PNPLA3 GG genotype. Finally, the presence of the PNPLA3 homozygosity flattened the accuracy of fibrosis-4 (FIB-4) in discriminating histological fibrosis stages. The PNPLA3 GG genotype may underpower the accuracy of NITs which include PLT count in identifying those patients with potentially reversible stages of fibrosis.
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- 2023
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7. The I148M PNPLA3 variant mitigates niacin beneficial effects: How the genetic screening in non-alcoholic fatty liver disease patients gains value
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Erika Paolini, Miriam Longo, Marica Meroni, Giada Tria, Annalisa Cespiati, Rosa Lombardi, Sara Badiali, Marco Maggioni, Anna Ludovica Fracanzani, and Paola Dongiovanni
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niacin ,PNPLA3 I148M ,nutrigenomic ,NAD ,dietary supplementation ,Nutrition. Foods and food supply ,TX341-641 - Abstract
BackgroundThe PNPLA3 p.I148M impact on fat accumulation can be modulated by nutrients. Niacin (Vitamin B3) reduced triglycerides synthesis in in vitro and in vivo NAFLD models.ObjectivesIn this study, we aimed to investigate the niacin-I148M polymorphism crosstalk in NAFLD patients and examine niacin’s beneficial effect in reducing fat by exploiting hepatoma cells with different PNPLA3 genotype.DesignWe enrolled 172 (Discovery cohort) and 358 (Validation cohort) patients with non-invasive and histological diagnosis of NAFLD, respectively. Dietary niacin was collected from food diary, while its serum levels were quantified by ELISA. Hepatic expression of genes related to NAD metabolism was evaluated by RNAseq in bariatric NAFLD patients (n = 183; Transcriptomic cohort). Hep3B (148I/I) and HepG2 (148M/M) cells were silenced (siHep3B) or overexpressed (HepG2I148+) for PNPLA3, respectively.ResultsIn the Discovery cohort, dietary niacin was significantly reduced in patients with steatosis ≥ 2 and in I148M carriers. Serum niacin was lower in subjects carrying the G at risk allele and negatively correlated with obesity. The latter result was confirmed in the Validation cohort. At multivariate analysis, the I148M polymorphism was independently associated with serum niacin, supporting that it may be directly involved in the modulation of its availability. siHep3B cells showed an impaired NAD biosynthesis comparable to HepG2 cells which led to lower niacin efficacy in clearing fat, supporting a required functional protein to guarantee its effectiveness. Conversely, the restoration of PNPLA3 Wt protein in HepG2I148+ cells recovered the NAD pathway and improved niacin efficacy. Finally, niacin inhibited de novo lipogenesis through the ERK1/2/AMPK/SIRT1 pathway, with the consequent SREBP1-driven PNPLA3 reduction only in Hep3B and HepG2I148M+ cells.ConclusionsWe demonstrated a niacin-PNPLA3 I148M interaction in NAFLD patients which possibly pave the way to vitamin B3 supplementation in those with a predisposing genetic background.
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- 2023
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8. Notch-mediated hepatocyte MCP-1 secretion causes liver fibrosis
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Jinku Kang, Jorge Postigo-Fernandez, KyeongJin Kim, Changyu Zhu, Junjie Yu, Marica Meroni, Brent Mayfield, Alberto Bartolomé, Dianne H. Dapito, Anthony W. Ferrante Jr., Paola Dongiovanni, Luca Valenti, Remi J. Creusot, and Utpal B. Pajvani
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Gastroenterology ,Metabolism ,Medicine - Abstract
Patients with nonalcoholic steatohepatitis (NASH) have increased expression of liver monocyte chemoattractant protein-1 (MCP-1), but its cellular source and contribution to various aspects of NASH pathophysiology remain debated. We demonstrated increased liver CCL2 (which encodes MCP-1) expression in patients with NASH, and commensurately, a 100-fold increase in hepatocyte Ccl2 expression in a mouse model of NASH, accompanied by increased liver monocyte-derived macrophage (MoMF) infiltrate and liver fibrosis. To test repercussions of increased hepatocyte-derived MCP-1, we generated hepatocyte-specific Ccl2-knockout mice, which showed reduced liver MoMF infiltrate as well as decreased liver fibrosis. Forced hepatocyte MCP-1 expression provoked the opposite phenotype in chow-fed wild-type mice. Consistent with increased hepatocyte Notch signaling in NASH, we observed a close correlation between markers of Notch activation and CCL2 expression in patients with NASH. We found that an evolutionarily conserved Notch/recombination signal binding protein for immunoglobulin kappa J region binding site in the Ccl2 promoter mediated transactivation of the Ccl2 promoter in NASH diet–fed mice. Increased liver MoMF infiltrate and liver fibrosis seen in opposite gain-of-function mice was ameliorated with concomitant hepatocyte Ccl2 knockout or CCR2 inhibitor treatment. Hepatocyte Notch activation prompts MCP-1–dependent increase in liver MoMF infiltration and fibrosis.
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- 2023
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9. Low Lipoprotein(a) Levels Predict Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease
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Marica Meroni, Miriam Longo, Rosa Lombardi, Erika Paolini, Chiara Macchi, Alberto Corsini, Cesare R. Sirtori, Anna Ludovica Fracanzani, Massimiliano Ruscica, and Paola Dongiovanni
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Dyslipidemia and cardiovascular complications are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis up to hepatocellular carcinoma. Lipoprotein(a) (Lp(a)) has been associated with cardiovascular risk and metabolic abnormalities, but its impact on the severity of liver damage in patients with NAFLD remains to be clarified. Circulating Lp(a) levels were assessed in 600 patients with biopsy‐proven NAFLD. The association of Lp(a) with liver damage was explored by categorizing serum Lp(a) into quartiles. The receiver operating characteristic curve was used to analyze the accuracy of serum Lp(a) in hepatic fibrosis prediction. Hepatic expression of lipoprotein A (LPA) and of genes involved in lipid metabolism and fibrogenic processes were evaluated by RNA sequencing in a subset of patients with NAFLD for whom Lp(a) dosage was available (n = 183). In patients with NAFLD, elevated Lp(a) levels were modestly associated with circulating lipids, carotid plaques, and hypertension (P
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- 2022
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10. TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro ModelsSummary
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Miriam Longo, Marica Meroni, Erika Paolini, Veronica Erconi, Fabrizia Carli, Francesco Fortunato, Dario Ronchi, Roberto Piciotti, Silvia Sabatini, Chiara Macchi, Anna Alisi, Luca Miele, Giorgio Soardo, Giacomo Pietro Comi, Luca Valenti, Massimiliano Ruscica, Anna L. Fracanzani, Amalia Gastaldelli, and Paola Dongiovanni
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NAFLD ,HCC ,TM6SF2 ,ER Stress ,Mitochondrial Dynamics ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: The I148M Patatin-like Phospholipase Domain-containing 3 (PNPLA3), the rs641738 in the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) locus, and the E167K Transmembrane 6 Superfamily Member 2 (TM6SF2) polymorphisms represent the main predisposing factors to nonalcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7-/-), homozygous for I148M PNPLA3. Therefore, we aimed to investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients, and create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7-/- cells. Methods: NAFLD patients (n = 1380), of whom 121 had HCC, were stratified with a semiquantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2, and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2-/-) and MBOAT7-/- (MBOAT7-/-TM6SF2-/-) through Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). Results: In NAFLD patients, the additive weight of these mutations was associated with liver disease severity and an increased risk of developing HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of microvesicular lipid droplets (LDs), whereas the MBOAT7-/-TM6SF2-/- cells showed a mixed microvesicular/macrovesicular pattern of LDs. TM6SF2 deletion strongly affected endoplasmic reticulum and mitochondria ultrastructures, thus increasing endoplasmic reticulum/oxidative stress. The mitochondrial number was increased in both TM6SF2-/- and MBOAT7-/-TM6SF2-/- models, suggesting an unbalancing in mitochondrial dynamics, and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift toward anaerobic glycolysis. MBOAT7-/-TM6SF2-/- cells also showed the highest proliferation rate. Finally, the re-overexpression of MBOAT7 and/or TM6SF2 reversed the metabolic and tumorigenic features observed in the compound knockout model. Conclusions: The co-presence of the 3 at-risk variants impacts the NAFLD course in both patients and experimental models, affecting LD accumulation, mitochondrial functionality, and metabolic reprogramming toward HCC.
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- 2022
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11. Expanding the phenotypic spectrum of non-alcoholic fatty liver disease and hypertriglyceridemia
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Marica Meroni, Miriam Longo, Erika Paolini, Giada Tria, Michela Ripolone, Laura Napoli, Maurizio Moggio, Anna Ludovica Fracanzani, and Paola Dongiovanni
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hypertriglyceridemia ,NAFLD ,whole-exome sequencing ,transmission electron microscopy ,mitochondrial dysfunction ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Background and aimsHypertriglyceridemia is a common feature of metabolic syndrome (MetS), as well as of non-alcoholic fatty liver disease (NAFLD), which is considered the hepatic manifestation of MetS. Fat accumulation in hepatocytes may alter mitochondrial homeostasis predisposing to advanced liver disease. Here, we report a case of a 40-year-old woman with early aggressive NAFLD due to severe hypertriglyceridemia that ensued from a combination of genetic variants and additional metabolic risk factors.MethodsGenetic screening was performed by using whole-exome sequencing (WES), and mitochondrial structures were evaluated by TEM.ResultsAt presentation, the patient is reported to have hepatomegaly, hypertriglyceridemia, and raised transaminases. Genetic analysis revealed that the patient beard heritable alterations in genes implicated in lipid handling, among which APOB, APOE, CETP, and HSPG2, accompanied by missense mutations in genes involved in mitochondrial function, i.e., AK2, ALG6, ASPA, NDUFAF1, POLG, and TMEM70. Abdominal ultrasound (US) and transient elastography were suggestive of severe hepatic steatosis and fibrosis. A liver biopsy confirmed the diagnosis of non-alcoholic steatohepatitis (NASH)-related fibrosis. Thus, to better outline whether mutations involved in lipid remodeling and mitochondrial function may also affect organelles’ morphology, we exploited TEM. Along with multifaceted abnormalities of mitochondrial architecture that have been already observed in patients with NAFLD, astonishing ultrastructural defects, such as mitochondrial vacuolization, sub-compartmentalization, and onion-like mitochondria, were identified.ConclusionThe anomalies reported may expand the phenotypic spectrum of mitochondrial abnormalities observed in patients with NAFLD, which may contribute to the switching toward a progressive disease.
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- 2022
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12. An Overview of Hepatocellular Carcinoma Surveillance Focusing on Non-Cirrhotic NAFLD Patients: A Challenge for Physicians
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Annalisa Cespiati, Felice Cinque, Marica Meroni, Rosa Lombardi, Paola Dongiovanni, and Anna Ludovica Fracanzani
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HCC surveillance ,non-cirrhosis ,NAFLD ,conventional imaging ,AFP ,new biomarkers ,Biology (General) ,QH301-705.5 - Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and it ranges from simple steatosis to hepatocellular carcinoma (HCC). HCC represents the first liver tumor and the third source of cancer death. In the next few years, the prevalence of NAFLD and consequently of HCC is estimated to increase, becoming a major public health problem. The NAFLD-HCC shows several differences compared to other causes of chronic liver disease (CLD), including the higher percentage of patients that develop HCC in the absence of liver cirrhosis. In HCC surveillance, the international guidelines suggest a six months abdominal ultrasound (US), with or without alpha-fetoprotein (AFP) evaluation, in patients with cirrhosis and in a subgroup of patients with chronic hepatitis B infection. However, this screening program reveals several limitations, especially in NAFLD patients. Thus, new biomarkers and scores have been proposed to overcome the limits of HCC surveillance. In this narrative review we aimed to explore the differences in the HCC features between NAFLD and non-NAFLD patients, and those between NAFLD-HCC developed in the cirrhotic and non-cirrhotic liver. Finally, we focused on the limits of tumor surveillance in NAFLD patients, and we explored the new biomarkers for the early diagnosis of HCC.
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- 2023
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13. Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease
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Marica Meroni, Miriam Longo, and Paola Dongiovanni
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mafld ,genetics ,personalized medicine ,polygenic risk scores ,Other systems of medicine ,RZ201-999 - Abstract
The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.
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- 2020
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14. PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients
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Paola Dongiovanni, Marica Meroni, Guido Baselli, Rosellina M. Mancina, Massimiliano Ruscica, Miriam Longo, Raffaela Rametta, Annalisa Cespiati, Serena Pelusi, Nicola Ferri, Valeria Ranzani, Valerio Nobili, Jussi Pihlajamaki, Anna Ludovica Fracanzani, Sara Badiali, Salvatore Petta, Silvia Fargion, Stefano Romeo, Julia Kozlitina, and Luca Valenti
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genes in lipid dysfunction ,genetics ,metabolic disease ,nonalcoholic fatty liver disease ,proprotein convertase subtilisin/kexin type 7 ,Biochemistry ,QD415-436 - Abstract
Dyslipidemia and altered iron metabolism are typical features of nonalcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. The aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases, and hepatic inflammation in the LBC (P < 0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (P < 0.05). The rs236918 C allele was associated with upregulation of a new “intra-PCSK7” long noncoding RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (P < 0.01), which correlated with triglycerides (P = 0.04). In HepG2 cells, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, transforming growth factor β pathway activation, and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/activity.
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- 2019
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15. The KLB rs17618244 gene variant is associated with fibrosing MAFLD by promoting hepatic stellate cell activation
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Nadia Panera, Marica Meroni, Miriam Longo, Annalisa Crudele, Luca Valenti, Emanuele Bellacchio, Luca Miele, Valentina D'Oria, Erika Paolini, Marco Maggioni, Anna Ludovica Fracanzani, Anna Alisi, and Paola Dongiovanni
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MAFLD ,Liver damage ,HSCS activation ,protein stability ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: The rs17618244 G>A β-Klotho (KLB) variant has been associated with increased risk of ballooning and inflammation in pediatric patients with metabolic associated fatty liver disease (MAFLD), by reducing KLB expression. In hepatocytes, KLB downregulation induced fat accumulation and the expression of inflammatory and lipotoxic genes. We aimed to examine firstly the impact of the KLB rs17618244 variation on liver damage in adult patients with MAFLD and secondly its effect on hepatic stellate cells (HSCs) activation. Methods: The impact of the KLB rs17618244 variant on histological liver damage was surveyed in a retrospective cohort of 1111 adult patients with MAFLD. Subgroup analysis was performed according to the presence of obesity (BMI>35; n = 708). Immortalized HSCs (LX-2) were transfected with the KLB wild type (LX-2_KLBwt), or with the mutant one carrying the rs17618244 (LX-2_KLBmut). Findings: At ordinal regression analysis the KLB rs17618244 variant was associated with hepatic fibrosis (OR 1.23, 95% C.I.1.004–1.51; p = 0.04), but not with steatosis, inflammation and ballooning. By stratifying patients according to the presence of obesity, the KLB A allele was further associated with lobular inflammation (OR 1.32, 95% C.I.1.02–1.72; p = 0.03) and cirrhosis (OR 2.51, 95% C.I.1.23–5.05; p = 0.01) Moreover, hepatic KLB expression correlated with that of fibrogenic genes. LX-2_KLBmut cells showed reduced KLB protein levels paralleled by an induction of pro-fibrogenic genes and enhanced proliferative rate. Interpretation: The KLB rs17618244 variant is associated with hepatic fibrosis, inflammation and cirrhosis mainly in obese patients with MAFLD and HSCs which carry this mutation are highly proliferative and acquire a myofibroblast-like phenotype. Funding: Ricerca Finalizzata Ministero della Salute GR-2019–12,370,172 (NP), Ricerca Corrente Fondazione IRCCS Cà Granda (PD and ALF), Ricerca Finalizzata Ministero della Salute RF-2013–02,358,319 (ALF), and Ricerca Corrente and 5 × 1000 Ministero della Salute (AA).
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- 2021
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16. Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution
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Miriam Longo, Erika Paolini, Marica Meroni, and Paola Dongiovanni
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AIP ,PBGD ,heme ,liver metabolism ,α-lipoic acid ,insulin ,Biology (General) ,QH301-705.5 - Abstract
Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by the hepatic deficiency of porphobilinogen deaminase (PBGD) and the slowdown of heme biosynthesis. AIP symptomatology includes life-threatening, acute neurovisceral or neuropsychiatric attacks manifesting in response to precipitating factors. The latter promote the upregulation of 5-aminolevulinic acid synthase-1 (ALAS1), the first enzyme of heme biosynthesis, which promotes the overload of neurotoxic porphyrin precursors. Hemin or glucose infusions are the first-line therapies for the reduction of ALAS1 levels in patients with mild to severe AIP, while liver transplantation is the only curative treatment for refractory patients. Recently, the RNA-interference against ALAS1 was approved as a treatment for adult and adolescent patients with AIP. These emerging therapies aim to substitute dysfunctional PBGD with adeno-associated vectors for genome editing, human PBGD mRNA encapsulated in lipid nanoparticles, or PBGD protein linked to apolipoprotein A1. Finally, the impairment of glucose metabolism linked to insulin resistance, and mitochondrial aberrations during AIP pathophysiology provided new therapeutic targets. Therefore, the use of liver-targeted insulin and insulin-mimetics such as α-lipoic acid may be useful for overcoming metabolic dysfunction in these subjects. Herein, the present review aims to provide an overview of AIP pathophysiology and management, focusing on conventional and recent therapeutical approaches.
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- 2022
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17. PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease
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Rosa Lombardi, Roberto Piciotti, Paola Dongiovanni, Marica Meroni, Silvia Fargion, and Anna Ludovica Fracanzani
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NAFLD ,NASH ,liver immune microenvironment ,PD-1 ,immune therapy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by an enhanced activation of the immune system, which predispose the evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Resident macrophages and leukocytes exert a key role in the pathogenesis of NAFLD. In particular, CD4+ effector T cells are activated during the early stages of liver inflammation and are followed by the increase of natural killer T cells and of CD8+ T cytotoxic lymphocytes which contribute to auto-aggressive tissue damage. To counteract T cells activation, programmed cell death 1 (PD-1) and its ligand PDL-1 are exposed respectively on lymphocytes and liver cells’ surface and can be targeted for therapy by using specific monoclonal antibodies, such as of Nivolumab, Pembrolizumab, and Atezolizumab. Despite the combination of Atezolizumab and Bevacizumab has been approved for the treatment of advanced HCC, PD-1/PD-L1 blockage treatment has not been approved for NAFLD and adjuvant immunotherapy does not seem to improve survival of patients with early-stage HCC. In this regard, different ongoing phase III trials are testing the efficacy of anti-PD-1/PD-L1 antibodies in HCC patients as first line therapy and in combination with other treatments. However, in the context of NAFLD, immune checkpoints inhibitors may not improve HCC prognosis, even worse leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Here, we will describe the main pathogenetic mechanisms which characterize the immune system involvement in NAFLD discussing advantages and obstacles of anti PD-1/PDL-1 immunotherapy.
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- 2022
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18. Impact of Sarcopenia and Myosteatosis in Non-Cirrhotic Stages of Liver Diseases: Similarities and Differences across Aetiologies and Possible Therapeutic Strategies
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Annalisa Cespiati, Marica Meroni, Rosa Lombardi, Giovanna Oberti, Paola Dongiovanni, and Anna Ludovica Fracanzani
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sarcopenia ,myosteatosis ,chronic liver disease ,NAFLD ,alcohol liver disease ,viral hepatitis ,Biology (General) ,QH301-705.5 - Abstract
Sarcopenia is defined as a loss of muscle strength, mass and function and it is a predictor of mortality. Sarcopenia is not only a geriatric disease, but it is related to several chronic conditions, including liver diseases in both its early and advanced stages. Despite the increasing number of studies exploring the role of sarcopenia in the early stages of chronic liver disease (CLD), its prevalence and the relationship between these two clinical entities are still controversial. Myosteatosis is characterized by fat accumulation in the muscles and it is related to advanced liver disease, although its role in the early stages is still under researched. Therefore, in this narrative review, we firstly aimed to evaluate the prevalence and the pathogenetic mechanisms underlying sarcopenia and myosteatosis in the early stage of CLD across different aetiologies (mainly non-alcoholic fatty liver disease, alcohol-related liver disease and viral hepatitis). Secondly, due to the increasing prevalence of sarcopenia worldwide, we aimed to revise the current and the future therapeutic approaches for the management of sarcopenia in CLD.
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- 2022
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19. MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD
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Marica Meroni, Miriam Longo, Anna L. Fracanzani, and Paola Dongiovanni
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MBOAT7 ,LPIAT1 ,MAFLD ,NASH ,Hyperinsulinemia ,Insulin resistance ,Medicine ,Medicine (General) ,R5-920 - Abstract
Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, which include steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, that is a critical risk factor for hepatocellular carcinoma (HCC) development. Its pathogenesis is intertwined with obesity and type 2 diabetes (T2D). However, the predisposition to develop MAFLD is severely influenced by environmental and inherited cues. The rs641738 variant close to MBOAT7 gene has been identified by a genome-wide association screening in heavy drinkers. Although this variant has been associated with the entire spectrum of MAFLD, these results have not been completely replicated and the debate is still opened. Thus, functional studies that unravel the biological mechanisms underlying the genetic association with fatty liver are required. This review aims to summarize the clinical and experimental findings regarding the rs641738 variation and MBOAT7 function, with the purpose to shed light to its role as novel player in MAFLD pathophysiology.
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- 2020
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20. Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
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Marica Meroni, Paola Dongiovanni, Miriam Longo, Fabrizia Carli, Guido Baselli, Raffaela Rametta, Serena Pelusi, Sara Badiali, Marco Maggioni, Melania Gaggini, Anna Ludovica Fracanzani, Stefano Romeo, Stefano Gatti, Nicholas O. Davidson, Amalia Gastaldelli, and Luca Valenti
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation. Methods: Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes. Findings: In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype. Interpretation: MBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1. Funding: LV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016–02,364,358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-“Liver Investigation: Testing Marker Utility in Steatohepatitis”. MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) ‘Mario Coppo’ fellowship. Keywords: LPIAT1, NAFLD, Nash, Nonalcoholic fatty liver disease, Steatohepatitis, Phospholipid, Phosphatidylinositol
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- 2020
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21. Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC
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Paola Dongiovanni, Marica Meroni, Miriam Longo, Silvia Fargion, and Anna Ludovica Fracanzani
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NAFLD ,NASH ,heritability ,HCC ,nutrition ,Biology (General) ,QH301-705.5 - Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients’ health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.
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- 2021
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22. Genetics Is of the Essence to Face NAFLD
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Marica Meroni, Miriam Longo, Giada Tria, and Paola Dongiovanni
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NAFLD ,heritability ,personalized medicine ,lipid handling ,polygenic risk scores ,Biology (General) ,QH301-705.5 - Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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- 2021
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23. α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study
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Miriam Longo, Erika Paolini, Marica Meroni, Lorena Duca, Irene Motta, Anna Ludovica Fracanzani, Elena Di Pierro, and Paola Dongiovanni
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AIP ,PBGD ,glucose metabolism ,mitobiogenesis ,α-lipoic acid ,Medicine (General) ,R5-920 - Abstract
Background: Acute intermittent porphyria (AIP) is caused by the haploinsufficiency of porphobilinogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting, and alterations in glucose metabolism, insulin resistance, and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin mimic, α-lipoic acid (α-LA), as a potential therapeutic strategy. Methods: HepG2 cells were transfected with siRNA-targeting PBGD (siPBGD). Cells were cultured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glucose. Results: At baseline, siPBGD cells showed a lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced glycolysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mitochondrial separation. Consistently, siPBGD cells in the fasted state showed the lowest protein levels of Complex IV, which belongs to the oxidative phosphorylation (OXPHOS) machinery. α-LA upregulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity, and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dysfunctions in siPBGD hepatocytes.
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- 2021
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24. The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients
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Marica Meroni, Miriam Longo, Erika Paolini, Anna Alisi, Luca Miele, Emilia Rita De Caro, Giuseppina Pisano, Marco Maggioni, Giorgio Soardo, Luca Vittorio Valenti, Anna Ludovica Fracanzani, and Paola Dongiovanni
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lipid metabolism ,NAFLD ,genetic variants ,PSRC1 ,HCC ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background and Aims: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n = 125). Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR): 5.62; 95% c.i. 1.77–17.84, p = 0.003), poor prognosis and advanced tumor stage (p < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p < 0.05). Conclusions: In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.
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- 2021
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25. Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC
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Miriam Longo, Erika Paolini, Marica Meroni, and Paola Dongiovanni
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NAFLD ,NASH ,HCC ,mitochondrial dynamics ,hepatocytes ,KCs ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic–lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.
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- 2021
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26. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals
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Benedetta Donati, Paola Dongiovanni, Stefano Romeo, Marica Meroni, Misti McCain, Luca Miele, Salvatore Petta, Silvia Maier, Chiara Rosso, Laura De Luca, Ester Vanni, Stefania Grimaudo, Renato Romagnoli, Fabio Colli, Flaminia Ferri, Rosellina Margherita Mancina, Paula Iruzubieta, Antonio Craxi, Anna Ludovica Fracanzani, Antonio Grieco, Stefano Ginanni Corradini, Alessio Aghemo, Massimo Colombo, Giorgio Soardo, Elisabetta Bugianesi, Helen Reeves, Quentin M. Anstee, Silvia Fargion, and Luca Valenti
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Medicine ,Science - Abstract
Abstract Nonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08–2.55; n = 765), particularly in those without advanced fibrosis (p
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- 2017
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27. From Environment to Genome and Back: A Lesson from HFE Mutations
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Raffaela Rametta, Marica Meroni, and Paola Dongiovanni
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Hereditary hemochromatosis ,HFE ,iron metabolism ,polyphenols ,vitamins ,miRNAs ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The environment and the human genome are closely entangled and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, the selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for diseases. Hereditary hemochromatosis (HH) is a potentially lethal disease leading to iron accumulation mostly due to mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype. However, both penetrance of the C282Y variant and the clinical manifestation of the disease are extremely variable, suggesting that other genetic, epigenetic and environmental factors play a role in the development of HH, as well as, and in its progression to end-stage liver diseases. Alcohol consumption and dietary habits may impact on the phenotypic expression of HFE-related hemochromatosis. Indeed, dietary components and bioactive molecules can affect iron status both directly by modulating its absorption during digestion and indirectly by the epigenetic modification of genes involved in its uptake, storage and recycling. Thus, the premise of this review is to discuss how environmental pressures led to the selection of HFE mutations and whether nutritional and lifestyle interventions may exert beneficial effects on HH outcomes and comorbidities.
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- 2020
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28. Nutrition and Genetics in NAFLD: The Perfect Binomium
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Marica Meroni, Miriam Longo, Alice Rustichelli, and Paola Dongiovanni
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nonalcoholic fatty liver disease ,nutrigenomics ,nutrigenetics ,nutriepigenomics ,gene-diet interaction ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a global healthcare burden since it is epidemiologically related to obesity, type 2 diabetes (T2D) and Metabolic Syndrome (MetS). It embraces a wide spectrum of hepatic injuries, which include simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The susceptibility to develop NAFLD is highly variable and it is influenced by several cues including environmental (i.e., dietary habits and physical activity) and inherited (i.e., genetic/epigenetic) risk factors. Nonetheless, even intestinal microbiota and its by-products play a crucial role in NAFLD pathophysiology. The interaction of dietary exposure with the genome is referred to as ‘nutritional genomics,’ which encompasses both ‘nutrigenetics’ and ‘nutriepigenomics.’ It is focused on revealing the biological mechanisms that entail both the acute and persistent genome-nutrient interactions that influence health and it may represent a promising field of study to improve both clinical and health nutrition practices. Thus, the premise of this review is to discuss the relevance of personalized nutritional advices as a novel therapeutic approach in NAFLD tailored management.
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- 2020
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29. The Role of Probiotics in Nonalcoholic Fatty Liver Disease: A New Insight into Therapeutic Strategies
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Marica Meroni, Miriam Longo, and Paola Dongiovanni
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nonalcoholic fatty liver disease ,gut microbiota ,gut–liver axis ,leaky gut ,intestinal permeability ,tight junctions ,endotoxemia ,probiotics ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of pathological hepatic conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which may predispose to liver cirrhosis and hepatocellular carcinoma (HCC). Due to the epidemic obesity, NAFLD is representing a global health issue and the leading cause of liver damage worldwide. The pathogenesis of NAFLD is closely related to insulin resistance (IR), adiposity and physical inactivity as well as genetic and epigenetic factors corroborate to the development and progression of hepatic steatosis and liver injury. Emerging evidence has outlined the implication of gut microbiota and gut-derived endotoxins as actively contributors to NAFLD pathophysiology probably due to the tight anatomo-functional crosstalk between the gut and the liver. Obesity, nutrition and environmental factors might alter intestinal permeability producing a favorable micro-environment for bacterial overgrowth, mucosal inflammation and translocation of both invasive pathogens and harmful byproducts, which, in turn, influence hepatic fat composition and exacerbated pro-inflammatory and fibrotic processes. To date, no therapeutic interventions are available for NAFLD prevention and management, except for modifications in lifestyle, diet and physical exercise even though they show discouraging results due to the poor compliance of patients. The premise of this review is to discuss the role of gut−liver axis in NAFLD and emphasize the beneficial effects of probiotics on gut microbiota composition as a novel attractive therapeutic strategy to introduce in clinical practice.
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- 2019
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30. mir-101-3p Downregulation Promotes Fibrogenesis by Facilitating Hepatic Stellate Cell Transdifferentiation During Insulin Resistance
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Marica Meroni, Miriam Longo, Veronica Erconi, Luca Valenti, Stefano Gatti, Anna Ludovica Fracanzani, and Paola Dongiovanni
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nafld ,fibrosis ,hcc ,hepatic stellate cells ,mir-101-3p ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+/−) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+/− mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+/− HSCs displayed 36 differentially expressed miRNAs (p < 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+/− mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+/− genotype and MCD (p < 0.05) and the histological spectrum of liver damage (p < 0.01). miR-101-3p was reduced in InsR+/− hepatocytes and HSCs and even more in InsR+/− cells exposed to insulin (0.33 µM) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+/− ones (p < 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation.
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- 2019
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31. Notch signaling and progenitor/ductular reaction in steatohepatitis.
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Carola M Morell, Romina Fiorotto, Marica Meroni, Aileen Raizner, Barbara Torsello, Massimiliano Cadamuro, Gaia Spagnuolo, Eleanna Kaffe, Salvatore Sutti, Emanuele Albano, and Mario Strazzabosco
- Subjects
Medicine ,Science - Abstract
Persistent hepatic progenitor cells (HPC) activation resulting in ductular reaction (DR) is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis.Steatohepatitis was generated using methionine-choline deficient (MCD) diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre.MCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-β1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent) Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-β1 treatment in primary hepatic stellate cells (HSC) induced Jag1 expression. In MCD diet-fed mice, αSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-β1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression.Our data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.
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- 2017
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32. Alcohol or Gut Microbiota: Who Is the Guilty?
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Marica Meroni, Miriam Longo, and Paola Dongiovanni
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alcoholic liver disease ,gut microbiota ,gut-liver axis ,leaky gut ,intestinal permeability ,tight junctions ,fecal microbiota transplantation ,target therapy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Alcoholic liver disease (ALD), a disorder caused by excessive alcohol intake represents a global health care burden. ALD encompasses a broad spectrum of hepatic injuries including asymptomatic steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The susceptibility of alcoholic patients to develop ALD is highly variable and its progression to more advanced stages is strongly influenced by several hits (i.e., amount and duration of alcohol abuse). Among them, the intestinal microbiota and its metabolites have been recently identified as paramount in ALD pathophysiology. Ethanol abuse triggers qualitative and quantitative modifications in intestinal flora taxonomic composition, mucosal inflammation, and intestinal barrier derangement. Intestinal hypermeability results in the translocation of viable pathogenic bacteria, Gram-negative microbial products, and pro-inflammatory luminal metabolites into the bloodstream, further corroborating the alcohol-induced liver damage. Thus, the premise of this review is to discuss the beneficial effect of gut microbiota modulation as a novel therapeutic approach in ALD management.
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- 2019
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33. Genetic and Epigenetic Modifiers of Alcoholic Liver Disease
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Marica Meroni, Miriam Longo, Raffaela Rametta, and Paola Dongiovanni
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alcoholic liver disease ,PNPLA3 ,TM6SF2 ,MBOAT7 ,microRNAs ,epigenetics ,intestinal permeability ,tight junctions ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Alcoholic liver disease (ALD), a disorder caused by excessive alcohol consumption is a global health issue. More than two billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders. ALD embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ALD is a complex disease where environmental, genetic, and epigenetic factors contribute to its pathogenesis and progression. The severity of alcohol-induced liver disease depends on the amount, method of usage and duration of alcohol consumption as well as on age, gender, presence of obesity, and genetic susceptibility. Genome-wide association studies and candidate gene studies have identified genetic modifiers of ALD that can be exploited as non-invasive biomarkers, but which do not completely explain the phenotypic variability. Indeed, ALD development and progression is also modulated by epigenetic factors. The premise of this review is to discuss the role of genetic variants and epigenetic modifications, with particular attention being paid to microRNAs, as pathogenic markers, risk predictors, and therapeutic targets in ALD.
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- 2018
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34. miRNA Signature in NAFLD: A Turning Point for a Non-Invasive Diagnosis
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Paola Dongiovanni, Marica Meroni, Miriam Longo, Silvia Fargion, and Anna Ludovica Fracanzani
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non-alcoholic liver disease ,NASH ,fibrosis ,HCC ,PNPLA3 ,TM6SF2 ,MBOAT7 ,microRNAs ,epigenetics ,intestinal permeability ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy but due to the high prevalence of NAFLD, this procedure, which is invasive, is not practicable for mass screening. Thus, it is crucial to non-invasively identify NAFLD patients at higher risk of progression to NASH and fibrosis. It has been demonstrated that hepatic fat content and progressive liver damage have a strong heritable component. Therefore, genetic variants associated with NAFLD have been proposed as non-invasive markers to be used in clinical practice. However, genetic variability is not completely explained by these common variants and it is possible that many of the phenotypic differences result from gene-environment interactions. Indeed, NAFLD development and progression is also modulated by epigenetic factors, in particular microRNAs (miRNAs), which control at post-transcriptional level many complementary target mRNAs and whose dysregulation has been shown to have high prognostic and predictive value in NAFLD. The premise of the current review is to discuss the role of miRNAs as pathogenic factors, risk predictors and therapeutic targets in NAFLD.
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- 2018
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35. Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease
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Rosaria M. Pipitone, Francesco Malvestiti, Grazia Pennisi, Oveis Jamialahmadi, Paola Dongiovanni, Giorgio Bertolazzi, Jussi Pihlajamäki, Hannele Yki‐Järvinen, Umberto Vespasiani‐Gentilucci, Federica Tavaglione, Samantha Maurotti, Cristiana Bianco, Gabriele Di Maria, Marco Enea, Anna L. Fracanzani, Vesa Kärjä, Giulia Lupo, Ville Männistö, Marica Meroni, Roberto Piciotti, Sami Qadri, Rossella Zito, Antonio Craxì, Vito Di Marco, Calogero Cammà, Claudio Tripodo, Luca Valenti, Stefano Romeo, Salvatore Petta, Stefania Grimaudo, Pipitone, Rosaria M, Malvestiti, Francesco, Pennisi, Grazia, Jamialahmadi, Ovei, Dongiovanni, Paola, Bertolazzi, Giorgio, Pihlajamäki, Jussi, Yki-Järvinen, Hannele, Vespasiani-Gentilucci, Umberto, Tavaglione, Federica, Maurotti, Samantha, Bianco, Cristiana, Di Maria, Gabriele, Enea, Marco, Fracanzani, Anna L, Kärjä, Vesa, Lupo, Giulia, Männistö, Ville, Meroni, Marica, Piciotti, Roberto, Qadri, Sami, Zito, Rossella, Craxì, Antonio, Di Marco, Vito, Cammà, Calogero, Tripodo, Claudio, Valenti, Luca, Romeo, Stefano, Petta, Salvatore, and Grimaudo, Stefania
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Settore MED/12 - Gastroenterologia ,Hepatology ,Settore BIO/13 - Biologia Applicata ,Gastroenterology ,CXCR6, NAFLD, NASH, PDCD1, checkpoint inhibitors - Abstract
Background and aims: Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy. Methods: We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNA-Seq in a subset of NAFLD individuals (n = 121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele. Results: The rs13023138 C>G showed the most robust association with HCC in UK Biobank (p = 5.28E-4, OR = 1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95% CI 1.02-1.34; p = .01), NASH (OR 1.22, 95% CI 1.09-1.37; p C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6. Conclusions: The PDCD1 rs13023138 G allele was associated with HCC development in the general population and with liver disease severity in patients at high risk of NASH.
- Published
- 2023
36. The overexpression of TM6SF2 and/or MBOAT7 wild-type genes re-establishes the mitochondrial dynamics in an in vitro NAFLD model
- Author
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Erika Paolini, Miriam Longo, Marica Meroni, Giada Tria, Chiara Macchi, Roberto Piciotti, Adele Agresta, Massimiliano Ruscica, Anna Ludovica Fracanzani, and Paola Dongiovanni
- Subjects
Hepatology - Published
- 2022
37. Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of
- Author
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Suraj J. Patel, Nan Liu, Sam Piaker, Anton Gulko, Maynara L. Andrade, Frankie D. Heyward, Tyler Sermersheim, Nufar Edinger, Harini Srinivasan, Margo P. Emont, Gregory P. Westcott, Jay Luther, Raymond T. Chung, Shuai Yan, Manju Kumari, Reeby Thomas, Yann Deleye, André Tchernof, Phillip J. White, Guido A. Baselli, Marica Meroni, Dario F. De Jesus, Rasheed Ahmad, Rohit N. Kulkarni, Luca Valenti, Linus Tsai, and Evan D. Rosen
- Subjects
viruses ,virus diseases ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Article ,Mice ,Glucose ,Liver ,Non-alcoholic Fatty Liver Disease ,Glucose Intolerance ,Humans ,Animals ,Interferon Regulatory Factor-3 ,Obesity ,Insulin Resistance - Abstract
Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b , a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.
- Published
- 2022
38. Recreating gut-liver axis during NAFLD onset by using a Caco-2/HepG2 co-culture system
- Author
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Marica Meroni, Erika Paolini, Miriam Longo, Roberto Piciotti, Giada Tria, Silvia Fargion, Anna Ludovica Fracanzani, and Paola Dongiovanni
- Subjects
digestive system - Abstract
Nonalcoholic fatty liver disease (NAFLD) onset and its progression towards nonalcoholic steatohepatitis (NASH) features increased intestinal permeability and leaky gut, thereby favoring the escape of endotoxin [lipopolysaccharides (LPS)] from the gut to the liver. The aim of this study was to resemble the crosstalk between intestine and liver during NAFLD by using an in vitro model of co-culture system. Enterocytes (Caco-2) were seeded on Transwell filters (pore size: 0.4 μm) and cultured for 21 days to constitute a confluent monolayer, and then they were co-cultivated with hepatocytes (HepG2) for an additional 24 h. Caco-2 on the apical chamber were exposed to LPS and/or a mixture of palmitic and oleic acid (PAOA) for 24 h. FITC-4000 dextrans (FD4) permeability across Caco-2 monolayer was increased by the treatment of Caco-2 cells with PAOA and LPS, consistently with tight junction-associated proteins reduction. Caco-2 exposure to PAOA/LPS promoted ApoB, triglyceride (TG), and free fatty acid secretion in basolateral media. In turn, HepG2 co-cultured with Caco-2 exposed to LPS, PAOA, or both accumulated lipid droplets and increased intracellular TG content. Likewise, Caco-2 released pro-inflammatory cytokines in basolateral media. These events triggered endoplasmic reticulum (ER) and oxidative stress, enhancing reactive oxygen species (ROS), H2O2, aldehyde derivate production, and ROS-induced DNA damage in HepG2 cells. Hence, Caco-2/HepG2 co-culture system may faithfully reproduce the breach in the intestinal barrier integrity that occurs in NAFLD, thus resulting in the increased inflammatory response and ER and oxidative and stress, which promote the switch towards NASH.
- Published
- 2022
39. Increased burden of inherited IRF3 rare genetic variants in Europeans with severe Non-alcoholic fatty liver diease
- Author
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Luigi Santoro, Daniele Marchelli, Alessandro Cherubini, Elia Casirati, Francesco Malvestiti, Melissa Tomasi, Paola Dongiovanni, Cristiana Bianco, Marica Meroni, Alessandro Federico, Salvatore Petta, Elisabetta Bugianesi, Giorgio Soardo, Umberto Vespasiani Gentilucci, Luca Miele, Helen Reeves, Daniele Prati, Luisa Ronzoni, Giodo Baselli, and Luca Valenti
- Subjects
Hepatology ,N/A ,Settore MED/12 - GASTROENTEROLOGIA - Published
- 2022
40. TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models
- Author
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Giacomo P. Comi, Amalia Gastaldelli, Roberto Piciotti, Anna Ludovica Fracanzani, S. Sabatini, Marica Meroni, Paola Dongiovanni, Massimiliano Ruscica, Giorgio Soardo, Anna Alisi, Luca Miele, Fabrizia Carli, Francesco Fortunato, Chiara Macchi, Veronica Erconi, Miriam Longo, Dario Ronchi, Erika Paolini, and Luca Valenti
- Subjects
BMI, body mass index ,PGC1α, Peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α ,RC799-869 ,Mitochondrion ,DMSO, dimethyl sulfoxide ,Mitochondrial Dynamics ,ApoB, apolipoprotein B-100 ,Liver disease ,PC, phosphatidylcholine ,MT-COX1, mitochondrially encoded cytochrome c oxidase subunit 1 ,PCR, polymerase chain reaction ,Non-alcoholic Fatty Liver Disease ,HCC ,ANOVA, analysis of variance ,Original Research ,GFP, green fluorescent protein ,Liver injury ,LDH, lactate dehydrogenase ,Fatty liver ,Liver Neoplasms ,Gastroenterology ,Single Nucleotide ,Diseases of the digestive system. Gastroenterology ,mRNA, messenger RNA ,Hepatocellular carcinoma ,Phospholipases A2, Calcium-Independent ,ER Stress ,SNP, single-nucleotide polymorphism ,NASH, nonalcoholic steatohepatitis ,Carcinoma, Hepatocellular ,ATP, adenosine triphosphate ,Genotype ,LD, lipid droplet ,TAG, triacylglycerol ,Settore MED/12 - GASTROENTEROLOGIA ,NAFLD ,TM6SF2 ,Calcium-Independent ,Cer, ceramide ,ORO, Oil Red O ,T2D, type 2 diabetes ,mTOR, mammalian target of rapamycin ,SDHA, succinate dehydrogenase complex flavoprotein subunit A ,Biology ,Polymorphism, Single Nucleotide ,PI, phosphatidylinositol ,ER, endoplasmic reticulum ,FBS, fetal bovine serum ,ORF, open reading frame ,NADH, nicotinamide adenine dinucleotide ,medicine ,Gene silencing ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,sgRNA, small guide RNA ,TEM, transmission electron microscopy ,PCA, principal component analysis ,Hepatology ,Carcinoma ,Membrane Proteins ,VLDL, very-low-density lipoprotein ,Hepatocellular ,Lipase ,medicine.disease ,digestive system diseases ,OR, odds ratio ,Phospholipases A2 ,Anaerobic glycolysis ,lyso, lysophosphatidylinositol ,Akt, protein kinase B ,CRISPR-Cas9, Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 ,Unfolded protein response ,Cancer research ,BSA, bovine serum albumin ,DMEM, Dulbecco’s modified Eagle medium ,NAFLD, nonalcoholic fatty liver disease ,HCC, hepatocellular carcinoma ,DAG, diacylglycerol ,Acyltransferases - Abstract
Background & Aims The I148M Patatin-like Phospholipase Domain-containing 3 (PNPLA3), the rs641738 in the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) locus, and the E167K Transmembrane 6 Superfamily Member 2 (TM6SF2) polymorphisms represent the main predisposing factors to nonalcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7-/-), homozygous for I148M PNPLA3. Therefore, we aimed to investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients, and create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7-/- cells. Methods NAFLD patients (n = 1380), of whom 121 had HCC, were stratified with a semiquantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2, and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2-/-) and MBOAT7-/- (MBOAT7-/-TM6SF2-/-) through Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). Results In NAFLD patients, the additive weight of these mutations was associated with liver disease severity and an increased risk of developing HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of microvesicular lipid droplets (LDs), whereas the MBOAT7-/-TM6SF2-/- cells showed a mixed microvesicular/macrovesicular pattern of LDs. TM6SF2 deletion strongly affected endoplasmic reticulum and mitochondria ultrastructures, thus increasing endoplasmic reticulum/oxidative stress. The mitochondrial number was increased in both TM6SF2-/- and MBOAT7-/-TM6SF2-/- models, suggesting an unbalancing in mitochondrial dynamics, and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift toward anaerobic glycolysis. MBOAT7-/-TM6SF2-/- cells also showed the highest proliferation rate. Finally, the re-overexpression of MBOAT7 and/or TM6SF2 reversed the metabolic and tumorigenic features observed in the compound knockout model. Conclusions The co-presence of the 3 at-risk variants impacts the NAFLD course in both patients and experimental models, affecting LD accumulation, mitochondrial functionality, and metabolic reprogramming toward HCC., Graphical abstract
- Published
- 2022
41. Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease
- Author
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Miriam Longo, Paola Dongiovanni, and Marica Meroni
- Subjects
0301 basic medicine ,business.industry ,Fatty liver ,personalized medicine ,Disease ,Bioinformatics ,medicine.disease ,Other systems of medicine ,03 medical and health sciences ,polygenic risk scores ,030104 developmental biology ,0302 clinical medicine ,medicine ,genetics ,030211 gastroenterology & hepatology ,mafld ,business ,RZ201-999 - Abstract
The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.
- Published
- 2020
42. MAFLD in COVID-19 patients: an insidious enemy
- Author
-
Anna Ludovica Fracanzani, Marica Meroni, Paola Dongiovanni, and Miriam Longo
- Subjects
Male ,medicine.medical_specialty ,Pneumonia, Viral ,Population ,Comorbidity ,Disease ,Global Health ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Prevalence ,medicine ,Humans ,Viral shedding ,Risk factor ,education ,Pandemics ,Aged ,Metabolic Syndrome ,education.field_of_study ,Hepatology ,SARS-CoV-2 ,business.industry ,Fatty liver ,Gastroenterology ,COVID-19 ,medicine.disease ,Fatty Liver ,Pneumonia ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Metabolic syndrome ,Coronavirus Infections ,business - Abstract
The pandemic Sars-CoV-2 infection represents a dramatic health challenge worldwide. Pneumonia is considered the major damage caused by the virus. However, recent data have highlighted the impact of the Sars-CoV-2 related disease namely COVID-19 on the liver. Hepatic abnormalities significantly increase during COVID-19 and a more severe infection occurs in patients with pre-existing liver diseases, among which the most frequent is metabolic-associated fatty liver disease (MAFLD). It has been described that MAFLD patients had a higher risk of progression to severe COVID-19, higher abnormal liver tests and longer viral shedding time. The presence of fibrosis in MAFLD patients is another risk factor for severity of COVID-19. Due to the overgrowing prevalence of MAFLD, it could be speculated that a large proportion of the population might be at risk of severe COVID-19 and the identification of these patients possibly by using liver enzymes as risk predictors may be crucial for an early diagnosis and for the management of the infection.
- Published
- 2020
43. MAFLD definition underestimates the risk to develop HCC in genetically predisposed patients
- Author
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Erika Paolini, Sara Badiali, Miriam Longo, Anna Ludovica Fracanzani, Rosa Lombardi, Paola Dongiovanni, Marco Maggioni, Paolo Francione, Roberto Piciotti, and Marica Meroni
- Subjects
medicine.medical_specialty ,Carcinoma, Hepatocellular ,business.industry ,Non-alcoholic Fatty Liver Disease ,Liver Neoplasms ,Internal Medicine ,medicine ,Humans ,Diagnostic accuracy ,Genetic Predisposition to Disease ,Intensive care medicine ,business - Published
- 2021
44. Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC
- Author
-
Anna Ludovica Fracanzani, Paola Dongiovanni, Miriam Longo, Marica Meroni, and Silvia Fargion
- Subjects
Cirrhosis ,QH301-705.5 ,business.industry ,NASH ,Medicine (miscellaneous) ,Review ,heritability ,medicine.disease ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,digestive system diseases ,nutrition ,Hepatocellular carcinoma ,NAFLD ,Nonalcoholic fatty liver disease ,medicine ,Liver function ,Biology (General) ,Steatohepatitis ,Steatosis ,HCC ,Liver cancer ,business ,Dysbiosis - Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients’ health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.
- Published
- 2021
45. α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study
- Author
-
Anna Ludovica Fracanzani, Miriam Longo, Irene Motta, Lorena Duca, Paola Dongiovanni, Erika Paolini, Marica Meroni, and Elena Di Pierro
- Subjects
medicine.medical_specialty ,Medicine (General) ,α-lipoic acid ,Chemistry ,Mitochondrial Turnover ,Insulin ,medicine.medical_treatment ,Communication ,glucose metabolism ,Clinical Biochemistry ,Oxidative phosphorylation ,Carbohydrate metabolism ,medicine.disease ,PBGD ,Metabolic pathway ,mitobiogenesis ,Endocrinology ,Insulin resistance ,R5-920 ,Internal medicine ,medicine ,Glycolysis ,AIP ,Acute intermittent porphyria - Abstract
Background: Acute intermittent porphyria (AIP) is caused by the haploinsufficiency of porphobilinogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting, and alterations in glucose metabolism, insulin resistance, and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin mimic, α-lipoic acid (α-LA), as a potential therapeutic strategy. Methods: HepG2 cells were transfected with siRNA-targeting PBGD (siPBGD). Cells were cultured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glucose. Results: At baseline, siPBGD cells showed a lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced glycolysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mitochondrial separation. Consistently, siPBGD cells in the fasted state showed the lowest protein levels of Complex IV, which belongs to the oxidative phosphorylation (OXPHOS) machinery. α-LA upregulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity, and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dysfunctions in siPBGD hepatocytes.
- Published
- 2021
46. Genetics Is of the Essence to Face NAFLD
- Author
-
Miriam Longo, Giada Tria, Marica Meroni, and Paola Dongiovanni
- Subjects
Cirrhosis ,business.industry ,QH301-705.5 ,lipid handling ,Medicine (miscellaneous) ,nutritional and metabolic diseases ,Review ,personalized medicine ,heritability ,medicine.disease ,Bioinformatics ,Chronic liver disease ,General Biochemistry, Genetics and Molecular Biology ,digestive system diseases ,Insulin resistance ,polygenic risk scores ,Fibrosis ,NAFLD ,Nonalcoholic fatty liver disease ,medicine ,Metabolic syndrome ,Biology (General) ,business ,Dyslipidemia ,TM6SF2 - Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
- Published
- 2021
47. Low Lipoprotein(a) Levels Predict Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease
- Author
-
Marica, Meroni, Miriam, Longo, Rosa, Lombardi, Erika, Paolini, Chiara, Macchi, Alberto, Corsini, Cesare R, Sirtori, Anna Ludovica, Fracanzani, Massimiliano, Ruscica, and Paola, Dongiovanni
- Subjects
Liver Cirrhosis ,Non-alcoholic Fatty Liver Disease ,Humans ,Proprotein Convertase 9 ,Fibrosis ,Transaminases ,Lipoprotein(a) - Abstract
Dyslipidemia and cardiovascular complications are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis up to hepatocellular carcinoma. Lipoprotein(a) (Lp(a)) has been associated with cardiovascular risk and metabolic abnormalities, but its impact on the severity of liver damage in patients with NAFLD remains to be clarified. Circulating Lp(a) levels were assessed in 600 patients with biopsy-proven NAFLD. The association of Lp(a) with liver damage was explored by categorizing serum Lp(a) into quartiles. The receiver operating characteristic curve was used to analyze the accuracy of serum Lp(a) in hepatic fibrosis prediction. Hepatic expression of lipoprotein A (LPA) and of genes involved in lipid metabolism and fibrogenic processes were evaluated by RNA sequencing in a subset of patients with NAFLD for whom Lp(a) dosage was available (n = 183). In patients with NAFLD, elevated Lp(a) levels were modestly associated with circulating lipids, carotid plaques, and hypertension (P 0.05). Conversely, patients with low serum Lp(a) displayed insulin resistance (P 0.05), transaminase elevation (P 0.05), and increased risk of developing severe fibrosis (P = 0.007) and cirrhosis (P = 0.002). In addition, the diagnostic accuracy of Lp(a) in predicting fibrosis increased by combining it with transaminases (area under the curve fibrosis stage 4, 0.87; P 0.0001). Hepatic LPA expression reflected serum Lp(a) levels (P = 0.018), and both were reduced with the progression of NAFLD (P 0.05). Hepatic LPA messenger RNA levels correlated with those of genes involved in lipoprotein release, lipid synthesis, and fibrogenesis (P 0.05). Finally, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, apolipoprotein E (ApoE) rs445925, and proprotein convertase subtilisin/kexin type 9 (PCSK9) rs7552841, known variants that modulate circulating lipids, may influence serum Lp(a) levels (P 0.05). Conclusion: Circulating Lp(a) combined with transaminases may represent a novel noninvasive biomarker to predict advanced fibrosis in patients with NAFLD.
- Published
- 2021
48. The α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study
- Author
-
Miriam Longo, Irene Motta, Anna Ludovica Fracanzani, Lorena Duca, Erika Paolini, Marica Meroni, Elena Di Pierro, and Paola Dongiovanni
- Subjects
Lipoic acid ,chemistry.chemical_compound ,chemistry ,business.industry ,allergology ,Alpha-Lipoic Acid ,Medicine ,Pharmacology ,Carbohydrate metabolism ,business ,medicine.disease ,Acute intermittent porphyria - Abstract
Background: Acute intermittent porphyria (AIP) is caused by haploinsufficiency of porphobilin-ogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting and altera-tions in glucose metabolism, insulin resistance and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin-mimic, the α-lipoic acid (α-LA) as a potential therapeutic strategy. Methods: HepG2 cells were transfected with a siRNA targeting PBGD (siPBGD). Cells were cul-tured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glu-cose. Results: At baseline, siPBGD cells showed lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced gly-colysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mito-chondrial separation. Consistently, siPBGD cells in fasted state showed the lowest protein levels of Complex IV which belong to the oxidative phosphorylation (OXPHOS) machinery. α-LA up-regulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dys-functions in siPBGD hepatocytes. Keywords: AIP, PBGD, glucose metabolism, mitobiogenesis, α-lipoic acid
- Published
- 2021
49. Comparison of hepatic and cardiovascular damage between HIV patients with steatosis and NAFLD: role of metabolic alterations and low visceral adiposity
- Author
-
Felice Cinque, Rosa Lombardi, Annalisa Cespiati, Paolo Francione, Erika Fatta, Cristina Bertelli, Giuseppina Pisano, Giovanna Oberti, Lucia Colavolpe, Francesca Alletto, Paola Dongiovanni, Marica Meroni, Giorgio Bozzi, Alessandra Bandera, and Anna Ludovica Fracanzani
- Subjects
Hepatology - Published
- 2022
50. The different modulation of KLB expression impacts on liver damage in NAFLD patients and in an in vitro model: a novel druggable target?
- Author
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Marica Meroni, Nadia Panera, Giada Tria, Roberto Piciotti, Miriam Longo, Erika Paolini, Antonella Mosca, Annalisa Crudele, Anna Ludovica Fracanzani, Anna Alisi, and Paola Dongiovanni
- Subjects
Hepatology - Published
- 2022
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