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Marcin Krawczyk - One of the best experts on this subject based on the ideXlab platform.
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could inherited predisposition drive non obese fatty liver disease results from german tertiary referral centers
Journal of Human Genetics, 2018Co-Authors: Marcin Krawczyk, Jorn M Schattenberg, Heike Bantel, Munevver Demir, Johannes Kluwe, Tobias Boettler, Frank Grunhage, Anita Pathil, S N WeberAbstract:Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20–72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.
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combined effects of the pnpla3 rs738409 tm6sf2 rs58542926 and MBOAT7 rs641738 variants on nafld severity a multicenter biopsy based study
Journal of Lipid Research, 2017Co-Authors: Marcin Krawczyk, Jorn M Schattenberg, Heike Bantel, Munevver Demir, Johannes Kluwe, Tobias Boettler, Frank Lammert, Anita Pathil, Andreas GeierAbstract:: The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16-88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P 0.05). The MBOAT7 variant was solely associated with increased fibrosis (P = 0.046). In the multivariate model, variants PNPLA3 (P = 0.004) and TM6SF2 (P = 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3 (P = 0.042) and MBOAT7 (P = 0.021) but not by the TM6SF2 polymorphism (P > 0.05). The PNPLA3, TM6SF2, and MBOAT7 variants are associated with increased liver injury. The TM6SF2 variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7 polymorphism is linked to fibrosis. The PNPLA3 polymorphism confers risk of both increased steatosis and fibrosis.
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pnpla3 p i148m variant is associated with greater reduction of liver fat content after bariatric surgery
Surgery for Obesity and Related Diseases, 2016Co-Authors: Marcin Krawczyk, R Jimenezaguero, Jose Antonio Mujika Alustiza, Jose I Emparanza, Maria J Perugorria, Luis BujandaAbstract:Abstract Background Obesity is the major trigger of nonalcoholic fatty liver disease (NAFLD). NAFLD is further favored by the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, transmembrane 6 superfamily member 2 (TM6SF2) p.E167K, and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 variants. Objectives To investigate the relationship between the PNPLA3, TM6SF2, and MBOAT7 genotypes and the outcomes of bariatric surgery. Setting University hospital. Methods Prospectively we monitored 84 obese individuals (body mass index 35–64 kg/m 2 ) scheduled for bariatric surgery. The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants were genotyped using restriction fragment length polymorphism analysis and TaqMan assays. Hepatic steatosis was determined before surgery using analysis of liver biopsy samples and a novel magnetic resonance imaging–based equation. One year later, steatosis was reevaluated by magnetic resonance imaging. Results The presence of the PNPLA3 allle [M] was associated with increased hepatic triglyceride content ( P = .03), steatosis detected by magnetic resonance imaging ( P = 0.04), and decreased serum glucose concentrations ( P = .04). Neither variant TM6SF2 nor MBOAT7 increased hepatic steatosis (all P >.05); however, the MBOAT7 polymorphism was associated with increased triglyceride, total cholesterol, low density lipoprotein, and serum glucose levels (all P P P = .04) one year after surgery, as compared to individuals having the common genotype. The PNPLA3 genotype and initial grade of steatosis, but not the TM6SF2 or MBOAT7 variants, were independent predictors of NAFLD improvement ( P = .03 and P Conclusion In obese patients, the presence of the PNPLA3 p.I148M allele might be associated with greater improvement of hepatic steatosis after bariatric surgery in comparison to carriers of PNPLA3 wild-type alleles.
Marica Meroni - One of the best experts on this subject based on the ideXlab platform.
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MBOAT7 down regulation by hyper insulinemia induces fat accumulation in hepatocytes
EBioMedicine, 2020Co-Authors: Miriam Longo, Fabrizia Carli, Guido Baselli, Paola Dongiovanni, Marica Meroni, Serena Pelusi, Raffaela RamettaAbstract: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.
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MBOAT7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes: MBOAT7 reduction and hepatic steatosis
'Elsevier BV', 2020Co-Authors: Marica Meroni, Miriam Longo, Fabrizia Carli, Guido Baselli, Paola Dongiovanni, Serena Pelusi, Raffaela Rametta, S. Badiali, M. Maggioni, M. GagginiAbstract: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\u201302,364,358, Ricerca corrente Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-\u201cLiver Investigation: Testing Marker Utility in Steatohepatitis\u201d. MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) \u2018Mario Coppo\u2019 fellowship
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the MBOAT7 tmc4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent
Gastroenterology, 2016Co-Authors: Rosellina Margherita Mancina, Paola Dongiovanni, Marica Meroni, Raffaela Rametta, Salvatore Petta, Piero Pingitore, Jan Boren, Tiziana Montalcini, Arturo Pujia, Olov WiklundAbstract:Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7−TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7−TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.
Serena Pelusi - One of the best experts on this subject based on the ideXlab platform.
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MBOAT7 down regulation by hyper insulinemia induces fat accumulation in hepatocytes
EBioMedicine, 2020Co-Authors: Miriam Longo, Fabrizia Carli, Guido Baselli, Paola Dongiovanni, Marica Meroni, Serena Pelusi, Raffaela RamettaAbstract: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.
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MBOAT7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes: MBOAT7 reduction and hepatic steatosis
'Elsevier BV', 2020Co-Authors: Marica Meroni, Miriam Longo, Fabrizia Carli, Guido Baselli, Paola Dongiovanni, Serena Pelusi, Raffaela Rametta, S. Badiali, M. Maggioni, M. GagginiAbstract: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\u201302,364,358, Ricerca corrente Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-\u201cLiver Investigation: Testing Marker Utility in Steatohepatitis\u201d. MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) \u2018Mario Coppo\u2019 fellowship
Paola Dongiovanni - One of the best experts on this subject based on the ideXlab platform.
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MBOAT7 down regulation by hyper insulinemia induces fat accumulation in hepatocytes
EBioMedicine, 2020Co-Authors: Miriam Longo, Fabrizia Carli, Guido Baselli, Paola Dongiovanni, Marica Meroni, Serena Pelusi, Raffaela RamettaAbstract: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.
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MBOAT7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes: MBOAT7 reduction and hepatic steatosis
'Elsevier BV', 2020Co-Authors: Marica Meroni, Miriam Longo, Fabrizia Carli, Guido Baselli, Paola Dongiovanni, Serena Pelusi, Raffaela Rametta, S. Badiali, M. Maggioni, M. GagginiAbstract: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\u201302,364,358, Ricerca corrente Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-\u201cLiver Investigation: Testing Marker Utility in Steatohepatitis\u201d. MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) \u2018Mario Coppo\u2019 fellowship
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MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals
'Springer Science and Business Media LLC', 2017Co-Authors: B. Donati, Paola Dongiovanni, M. Meroni, S. Romeo, M. Mccain, L. Miele, S. Petta, S. Maier, C. Rosso, L. De LucaAbstract: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 < 0.001). The risk T allele was linked to 3'-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical factors (p < 0.001), but did not significantly improve their predictive accuracy. When combining data from an independent UK NAFLD cohort, in the overall cohort of non-cirrhotic patients (n = 913, 41 with HCC) the T allele remained associated with HCC (OR 2.10, 1.33-3.31). Finally, in a combined cohort of non-cirrhotic patients with chronic hepatitis C or alcoholic liver disease (n = 1121), the T allele was independently associated with HCC risk (OR 1.93, 1.07-3.58). In conclusion, the MBOAT7 rs641738 T allele is associated with reduced MBOAT7 expression and may predispose to HCC in patients without cirrhosis, suggesting it should be evaluated in future prospective studies aimed at stratifying NAFLD-HCC risk
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the MBOAT7 tmc4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent
Gastroenterology, 2016Co-Authors: Rosellina Margherita Mancina, Paola Dongiovanni, Marica Meroni, Raffaela Rametta, Salvatore Petta, Piero Pingitore, Jan Boren, Tiziana Montalcini, Arturo Pujia, Olov WiklundAbstract:Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7−TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7−TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.
Raffaela Rametta - One of the best experts on this subject based on the ideXlab platform.
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MBOAT7 down regulation by hyper insulinemia induces fat accumulation in hepatocytes
EBioMedicine, 2020Co-Authors: Miriam Longo, Fabrizia Carli, Guido Baselli, Paola Dongiovanni, Marica Meroni, Serena Pelusi, Raffaela RamettaAbstract: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.
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MBOAT7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes: MBOAT7 reduction and hepatic steatosis
'Elsevier BV', 2020Co-Authors: Marica Meroni, Miriam Longo, Fabrizia Carli, Guido Baselli, Paola Dongiovanni, Serena Pelusi, Raffaela Rametta, S. Badiali, M. Maggioni, M. GagginiAbstract: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\u201302,364,358, Ricerca corrente Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-\u201cLiver Investigation: Testing Marker Utility in Steatohepatitis\u201d. MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) \u2018Mario Coppo\u2019 fellowship
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the MBOAT7 tmc4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent
Gastroenterology, 2016Co-Authors: Rosellina Margherita Mancina, Paola Dongiovanni, Marica Meroni, Raffaela Rametta, Salvatore Petta, Piero Pingitore, Jan Boren, Tiziana Montalcini, Arturo Pujia, Olov WiklundAbstract:Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7−TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7−TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.