For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
2
views
29
references
 Top references
cited by
33
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      342
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes

      research-article
      Author(s): a , b , a , a , c , d , b , a , b , e , f , g , d , a , b , h , i , j , k , l , d , b , e , *
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: LPIAT1, NAFLD, Nash, Nonalcoholic fatty liver disease, Steatohepatitis, Phospholipid, Phosphatidylinositol, ALD, alcoholic liver disease, APOB, Apolipoprotein B, BMI, Body Mass Index, CDP, Cytidine-Diphosphate, CI, Confidence Interval, CL, Cardiolipin, CPT1, Carnitine Palmitoyltransferase I, CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats, CXCL10, C-X-C Motif Chemokine 10, DAG, Diacylglycerol, FABP1, Fatty Acid-Binding Protein 1, FAS, Fatty Acid Synthase, FATP1, Fatty Acid Transport Protein 1, FOXO1, Forkhead Box protein O1, FOXA2, Forkhead Box A2, G3P, Glyceraldehyde-3-Phosphate, HDL, High Density Lipoproteins, hHEPS, Human Hepatocytes, hHSC, Human Hepatic Stellate Cells, HOMA-IR, homeostasis Model Assessment of Insulin Resistance, IFG, Impaired Fasting Glucose, i.p., Intraperitoneal, i.v., Intravenous, LDL, Low Density Lipoproteins, LPA, Lyso-Phosphatidic Acid, LPIAT1, Lysophosphatidylinositol Acyltransferase 1, Mboat7, Membrane bound O-acyltransferase domain containing 7, MCD, methionine choline deficient diet, MPO, morpholino, mTOR, mammalian target of Rapamycin, MTTP, Microsomal Triglyceride Transfer Protein, NAFLD, nonalcoholic fatty liver disease, NASH, Nonalcoholic Steatohepatitis, NHEJ, Non-Homologues End Joining, OA, Oleic Acid, PA, Palmitic Acid, PC, Phosphatidylcholine, ORO, Oil Red O Staining, PE, Phosphatidyl-Ethanolamine, PG, Phosphatidyl-Glycerol, PI, Phosphatidylinositol, PIP, Phosphatidyl-Inositol-Phosphate, PI3K, Phosphatidylinositol 3 Kinase, PNPLA3, Patatin-like Phospholipase Domain-containing-3, PPARα, Peroxisome Proliferator-Activated Receptor alpha, PS, Phosphatidyl-Serine, qRT-PCR, quantitative Real Time Polymerase Chain Reaction, SD, Standard Diet, SREBP1c, Sterol Regulatory Element-Binding Protein 1, TAG, Triglycerides, TGFβ, Transforming Growth Factor Beta, TM6SF2, Transmembrane 6 Superfamily Member 2, TMC4, Transmembrane Channel-Like 4, TNFα, tumor Necrosis Factor Alpha, T2DM, Type 2 Diabetes Mellitus, VLDL, Very Low Density Lipoprotein

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT 7), 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.

          Related collections

          Most cited references29

          • Record: found
          • Abstract: found
          • Article: not found

          Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

          Stefano Romeo, Julia Kozlitina, Chao Xing … (2008)
          Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; I148M) was strongly associated with increased hepatic fat levels (P=5.9×10−10) and with hepatic inflammation (P=3.7×10−4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.
          Article 0 comments Cited 971 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.

            Rosellina Mancina, Paola Dongiovanni, Salvatore Petta … (2016)
            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.
            Article 0 comments Cited 267 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found

              A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

              Stephan Buch, Felix Stickel, Eric Trépo … (2015)
              Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.
              Article 0 comments Cited 196 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Luca Valenti
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 12 February 2020
                Publication date Collection: February 2020
                Publication date (Electronic): 12 February 2020
                Volume: 52
                Electronic Location Identifier: 102658
                Affiliations
                [a ]General and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
                [b ]Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy
                [c ]Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
                [d ]National Research Council (CNR), Institute of Clinical Physiology, Pisa, Italy
                [e ]Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Italy
                [f ]Department of Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
                [g ]Department of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
                [h ]Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
                [i ]Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden
                [j ]Clinical Nutrition Department of Medical and Surgical Science, University Magna Graecia, Catanzaro, Italy
                [k ]Preclinical research center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
                [l ]Department of Medicine, Washington University School of Medicine, St. Louis, MO, Italy
                Author notes
                [* ]Corresponding author at: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy. luca.valenti@ 123456unimi.it
                Article
                Publisher ID: S2352-3964(20)30033-5 Publisher ID: 102658
                DOI: 10.1016/j.ebiom.2020.102658
                PMC ID: 7026742
                PubMed ID: 32058943
                SO-VID: bd68c58f-3e5f-4f7d-9ea0-190b2fb16bd2
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 18 October 2019
                Date revision received : 21 January 2020
                Date accepted : 22 January 2020
                Categories
                Subject: Research paper

                Keywords: lpiat1,nafld,nash,nonalcoholic fatty liver disease,steatohepatitis,phospholipid,phosphatidylinositol,ald, alcoholic liver disease,apob, apolipoprotein b,bmi, body mass index,cdp, cytidine-diphosphate,ci, confidence interval,cl, cardiolipin,cpt1, carnitine palmitoyltransferase i,crispr, clustered regularly interspaced short palindromic repeats,cxcl10, c-x-c motif chemokine 10,dag, diacylglycerol,fabp1, fatty acid-binding protein 1, fas, fatty acid synthase,fatp1, fatty acid transport protein 1,foxo1, forkhead box protein o1,foxa2, forkhead box a2,g3p, glyceraldehyde-3-phosphate,hdl, high density lipoproteins,hheps, human hepatocytes,hhsc, human hepatic stellate cells,homa-ir, homeostasis model assessment of insulin resistance,ifg, impaired fasting glucose,i.p., intraperitoneal,i.v., intravenous,ldl, low density lipoproteins,lpa, lyso-phosphatidic acid,lpiat1, lysophosphatidylinositol acyltransferase 1,mboat7, membrane bound o-acyltransferase domain containing 7,mcd, methionine choline deficient diet,mpo, morpholino,mtor, mammalian target of rapamycin,mttp, microsomal triglyceride transfer protein,nafld, nonalcoholic fatty liver disease,nash, nonalcoholic steatohepatitis,nhej, non-homologues end joining,oa, oleic acid,pa, palmitic acid,pc, phosphatidylcholine,oro, oil red o staining,pe, phosphatidyl-ethanolamine,pg, phosphatidyl-glycerol,pi, phosphatidylinositol,pip, phosphatidyl-inositol-phosphate,pi3k, phosphatidylinositol 3 kinase,pnpla3, patatin-like phospholipase domain-containing-3,pparα, peroxisome proliferator-activated receptor alpha,ps, phosphatidyl-serine,qrt-pcr, quantitative real time polymerase chain reaction,sd, standard diet,srebp1c, sterol regulatory element-binding protein 1,tag, triglycerides,tgfβ, transforming growth factor beta,tm6sf2, transmembrane 6 superfamily member 2,tmc4, transmembrane channel-like 4,tnfα, tumor necrosis factor alpha,t2dm, type 2 diabetes mellitus,vldl, very low density lipoprotein
                Data availability:
                Keywords: lpiat1, nafld, nash, nonalcoholic fatty liver disease, steatohepatitis, phospholipid, phosphatidylinositol, ald, alcoholic liver disease, apob, apolipoprotein b, bmi, body mass index, cdp, cytidine-diphosphate, ci, confidence interval, cl, cardiolipin, cpt1, carnitine palmitoyltransferase i, crispr, clustered regularly interspaced short palindromic repeats, cxcl10, c-x-c motif chemokine 10, dag, diacylglycerol, fabp1, fatty acid-binding protein 1, fas, fatty acid synthase, fatp1, fatty acid transport protein 1, foxo1, forkhead box protein o1, foxa2, forkhead box a2, g3p, glyceraldehyde-3-phosphate, hdl, high density lipoproteins, hheps, human hepatocytes, hhsc, human hepatic stellate cells, homa-ir, homeostasis model assessment of insulin resistance, ifg, impaired fasting glucose, i.p., intraperitoneal, i.v., intravenous, ldl, low density lipoproteins, lpa, lyso-phosphatidic acid, lpiat1, lysophosphatidylinositol acyltransferase 1, mboat7, membrane bound o-acyltransferase domain containing 7, mcd, methionine choline deficient diet, mpo, morpholino, mtor, mammalian target of rapamycin, mttp, microsomal triglyceride transfer protein, nafld, nonalcoholic fatty liver disease, nash, nonalcoholic steatohepatitis, nhej, non-homologues end joining, oa, oleic acid, pa, palmitic acid, pc, phosphatidylcholine, oro, oil red o staining, pe, phosphatidyl-ethanolamine, pg, phosphatidyl-glycerol, pi, phosphatidylinositol, pip, phosphatidyl-inositol-phosphate, pi3k, phosphatidylinositol 3 kinase, pnpla3, patatin-like phospholipase domain-containing-3, pparα, peroxisome proliferator-activated receptor alpha, ps, phosphatidyl-serine, qrt-pcr, quantitative real time polymerase chain reaction, sd, standard diet, srebp1c, sterol regulatory element-binding protein 1, tag, triglycerides, tgfβ, transforming growth factor beta, tm6sf2, transmembrane 6 superfamily member 2, tmc4, transmembrane channel-like 4, tnfα, tumor necrosis factor alpha, t2dm, type 2 diabetes mellitus, vldl, very low density lipoprotein

                Comments

                Comment on this article

                scite_

                Similar content342

                See all similar

                Cited by33

                See all cited by

                Most referenced authors948

                See all reference authors