RT Journal Article
SR Electronic
T1 Loss of hepatic Mboat7 leads to liver fibrosis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 940
OP 950
DO 10.1136/gutjnl-2020-320853
VO 70
IS 5
A1 Thangapandi, Veera Raghavan
A1 Knittelfelder, Oskar
A1 Brosch, Mario
A1 Patsenker, Eleonora
A1 Vvedenskaya, Olga
A1 Buch, Stephan
A1 Hinz, Sebastian
A1 Hendricks, Alexander
A1 Nati, Marina
A1 Herrmann, Alexander
A1 Rekhade, Devavrat Ravindra
A1 Berg, Thomas
A1 Matz-Soja, Madlen
A1 Huse, Klaus
A1 Klipp, Edda
A1 Pauling, Josch K
A1 Wodke, Judith AH
A1 Miranda Ackerman, Jacobo
A1 Bonin, Malte von
A1 Aigner, Elmar
A1 Datz, Christian
A1 von Schönfels, Witigo
A1 Nehring, Sophie
A1 Zeissig, Sebastian
A1 Röcken, Christoph
A1 Dahl, Andreas
A1 Chavakis, Triantafyllos
A1 Stickel, Felix
A1 Shevchenko, Andrej
A1 Schafmayer, Clemens
A1 Hampe, Jochen
A1 Subramanian, Pallavi
YR 2021
UL http://gut.bmj.com/content/70/5/940.abstract
AB 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 (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.Results Allelic 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.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.Data are available on reasonable request. Not applicable.