Understanding the role of Mboat7 in liver disease

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

doi:10.1055/s-0041-1733629

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2021; 59(08): e214
DOI: 10.1055/s-0041-1733629

Translationale grundlagenorientierte Hepatologie

Donnerstag, 16. September 2021, 10:30-11:50

Leber und Galle

Understanding the role of Mboat7 in liver disease

VR Thangapandi

¹Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland

,

O Knittelfelder

²Max Planck Institute of Molecular Cell Biology and Genetic, Dresden, Deutschland

,

M Brosch

¹Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland

,

E Patsenker

³University Hospital of Zurich, Department of Gastroenterology and Hepatology, Zurich, Schweiz

,

O Vvedenskaya

²Max Planck Institute of Molecular Cell Biology and Genetic, Dresden, Deutschland

,

S Buch

¹Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland

,

S Hinz

⁴University of Rostock, Department of General, Visceral, Vascular and Transplantation Surgery, Rostock, Deutschland

,

A Hendricks

⁴University of Rostock, Department of General, Visceral, Vascular and Transplantation Surgery, Rostock, Deutschland

,

M Nati

⁵Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden (TU Dresden), Dresden, Deutschland

,

A Herrmann

¹Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland

,

Rekhade D Ravindra

¹Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland

,

T Berg

⁶Division of Hepatology, Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, Leipzig University Medical Center, Leipzig, Deutschland

,

M Matz-Soja

⁶Division of Hepatology, Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, Leipzig University Medical Center, Leipzig, Deutschland

,

K Huse

⁷Leibniz Institute for Ageing Research, Jena, Jena, Deutschland

,

E Klipp

⁸Theoretical Biophysics, Faculty of Biology, Humboldt-University Berlin, Berlin, Deutschland

,

J Pauling

⁹LipiTUM, Chair of Experimental Bioinformatics, Technical University of Munich, Freising, Deutschland

,

J Wodke

⁸Theoretical Biophysics, Faculty of Biology, Humboldt-University Berlin, Berlin, Deutschland

,

J Miranda Ackerman

²Max Planck Institute of Molecular Cell Biology and Genetic, Dresden, Deutschland

,

M von Bonin

¹⁰Technische Universität Dresden, Medical Department 1, Dresden, Deutschland

,

E Aigner

¹¹University Hospital Salzburg, Department of Internal Medicine I, Salzburg, Österreich

,

C Datz

¹²Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Department of Internal Medicine, Obernsdorf, Österreich

,

W von Schönfels

¹³University Hospital Schleswig-Holstein, Department of General and Thoracic Surgery, Kiel, Deutschland

,

S Nehring

¹Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland

,

S Zeissig

¹Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland

,

C Röcken

¹⁴Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Deutschland

,

A Dahl

¹⁵DRESDEN-concept Genome Center, c/o Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Deutschland

,

T Chavakis

⁵Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden (TU Dresden), Dresden, Deutschland

,

F Stickel

³University Hospital of Zurich, Department of Gastroenterology and Hepatology, Zurich, Schweiz

,

A Shevchenko

²Max Planck Institute of Molecular Cell Biology and Genetic, Dresden, Deutschland

,

C Schafmayer

⁴University of Rostock, Department of General, Visceral, Vascular and Transplantation Surgery, Rostock, Deutschland

,

J Hampe

¹Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland

,

P Subramanian

⁵Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden (TU Dresden), Dresden, Deutschland

› Author Affiliations

Abstract

Full Text

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 characterized by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analyzed 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 characterized 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< .05), hydroxyproline content (P< .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=.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 LPI and phosphatidylinositol subspecies in Mboat7^Δhep livers and humans 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 signaling and a potentially targetable treatment option in NAFLD.