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Thangapandi, V.R.* ; Knittelfelder, O.* ; Brosch, M.* ; Patsenker, E.* ; Vvedenskaya, O.* ; Buch, S.* ; Hinz, S.* ; Hendricks, A.* ; Nati, M.* ; Herrmann, A.* ; Rekhade, D.R.* ; Berg, T.* ; Matz-Soja, M.* ; Huse, K.* ; Klipp, E.* ; Pauling, J.K.* ; Wodke, J.A.* ; Miranda Ackerman, J.* ; Bonin, M.V.* ; Aigner, E.* ; Datz, C.* ; von Schönfels, W.* ; Nehring, S.* ; Zeissig, S.* ; Röcken, C.* ; Dahl, A.* ; Chavakis, T. ; Stickel, F.* ; Shevchenko, A.* ; Schafmayer, C.* ; Hampe, J.* ; Subramanian, P.*

Loss of hepatic Mboat7 leads to liver fibrosis.

Gut 70, 940-950 (2021)

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OBJECTIVE: The 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. DESIGN: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7^Δhep) 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. RESULTS: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7^Δhep 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 Mboat7^Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7^Δhep livers and human rs641738TT carriers were similar. CONCLUSION: Mboat7 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.

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