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 Veera Raghavan Thangapandi
A1 Oskar Knittelfelder
A1 Mario Brosch
A1 Eleonora Patsenker
A1 Olga Vvedenskaya
A1 Stephan Buch
A1 Sebastian Hinz
A1 Alexander Hendricks
A1 Marina Nati
A1 Alexander Herrmann
A1 Devavrat Ravindra Rekhade
A1 Thomas Berg
A1 Madlen Matz-Soja
A1 Klaus Huse
A1 Edda Klipp
A1 Josch K Pauling
A1 Judith AH Wodke
A1 Jacobo Miranda Ackerman
A1 Malte von Bonin
A1 Elmar Aigner
A1 Christian Datz
A1 Witigo von Schönfels
A1 Sophie Nehring
A1 Sebastian Zeissig
A1 Christoph Röcken
A1 Andreas Dahl
A1 Triantafyllos Chavakis
A1 Felix Stickel
A1 Andrej Shevchenko
A1 Clemens Schafmayer
A1 Jochen Hampe
A1 Pallavi Subramanian
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.