Loss of hepatic Mboat7 leads to liver fibrosis
Autor: | Judith A. H. Wodke, Oskar Knittelfelder, Jacobo Miranda Ackerman, Eleonora Patsenker, Malte von Bonin, Thomas Berg, Jochen Hampe, Alexander Hendricks, Veera Raghavan Thangapandi, Witigo von Schönfels, Triantafyllos Chavakis, Andreas Dahl, Elmar Aigner, S Nehring, Olga Vvedenskaya, A Herrmann, Andrej Shevchenko, Edda Klipp, Josch K. Pauling, Felix Stickel, Christian Datz, Pallavi Subramanian, Devavrat Ravindra Rekhade, Stephan Buch, Sebastian Hinz, Sebastian Zeissig, Clemens Schafmayer, Madlen Matz-Soja, Klaus Huse, Christoph Röcken, Marina Nati, Mario Brosch |
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Rok vydání: | 2020 |
Předmět: |
Male
Liver Cirrhosis 0301 basic medicine Biopsy Pathogenesis chemistry.chemical_compound Liver disease 0302 clinical medicine Non-alcoholic Fatty Liver Disease Fibrosis Fatty liver NASH Gastroenterology Middle Aged Hepatitis B 3. Good health Liver Disease Progression Lysophosphatidylinositol Female 030211 gastroenterology & hepatology Nafld Nash Liver Fibrosis Lipidomics Adult medicine.medical_specialty liver fibrosis lipidomics Genotype Polymorphism Single Nucleotide 03 medical and health sciences NAFLD Internal medicine medicine Animals Humans Aged Inflammation Hepatology business.industry Membrane Proteins medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology Haplotypes chemistry Steatosis Hepatic fibrosis business Acyltransferases |
Zdroj: | Gut Gut 70, 940-950 (2021) |
ISSN: | 1468-3288 0017-5749 |
Popis: | ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar.ConclusionMboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD. |
Databáze: | OpenAIRE |
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