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
1   Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland
,
O Knittelfelder
2   Max Planck Institute of Molecular Cell Biology and Genetic, Dresden, Deutschland
,
M Brosch
1   Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland
,
E Patsenker
3   University Hospital of Zurich, Department of Gastroenterology and Hepatology, Zurich, Schweiz
,
O Vvedenskaya
2   Max Planck Institute of Molecular Cell Biology and Genetic, Dresden, Deutschland
,
S Buch
1   Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland
,
S Hinz
4   University of Rostock, Department of General, Visceral, Vascular and Transplantation Surgery, Rostock, Deutschland
,
A Hendricks
4   University of Rostock, Department of General, Visceral, Vascular and Transplantation Surgery, Rostock, Deutschland
,
M Nati
5   Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden (TU Dresden), Dresden, Deutschland
,
A Herrmann
1   Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland
,
Rekhade D Ravindra
1   Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland
,
T Berg
6   Division of Hepatology, Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, Leipzig University Medical Center, Leipzig, Deutschland
,
M Matz-Soja
6   Division of Hepatology, Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, Leipzig University Medical Center, Leipzig, Deutschland
,
K Huse
7   Leibniz Institute for Ageing Research, Jena, Jena, Deutschland
,
E Klipp
8   Theoretical Biophysics, Faculty of Biology, Humboldt-University Berlin, Berlin, Deutschland
,
J Pauling
9   LipiTUM, Chair of Experimental Bioinformatics, Technical University of Munich, Freising, Deutschland
,
J Wodke
8   Theoretical Biophysics, Faculty of Biology, Humboldt-University Berlin, Berlin, Deutschland
,
J Miranda Ackerman
2   Max Planck Institute of Molecular Cell Biology and Genetic, Dresden, Deutschland
,
M von Bonin
10   Technische Universität Dresden, Medical Department 1, Dresden, Deutschland
,
E Aigner
11   University Hospital Salzburg, Department of Internal Medicine I, Salzburg, Österreich
,
C Datz
12   Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Department of Internal Medicine, Obernsdorf, Österreich
,
W von Schönfels
13   University Hospital Schleswig-Holstein, Department of General and Thoracic Surgery, Kiel, Deutschland
,
S Nehring
1   Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland
,
S Zeissig
1   Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland
,
C Röcken
14   Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Deutschland
,
A Dahl
15   DRESDEN-concept Genome Center, c/o Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Deutschland
,
T Chavakis
5   Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden (TU Dresden), Dresden, Deutschland
,
F Stickel
3   University Hospital of Zurich, Department of Gastroenterology and Hepatology, Zurich, Schweiz
,
A Shevchenko
2   Max Planck Institute of Molecular Cell Biology and Genetic, Dresden, Deutschland
,
C Schafmayer
4   University of Rostock, Department of General, Visceral, Vascular and Transplantation Surgery, Rostock, Deutschland
,
J Hampe
1   Universitätsklinikum Dresden, Gastroenterologie und Hepatologie MK1, Dresden, Deutschland
,
P Subramanian
5   Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden (TU Dresden), Dresden, Deutschland
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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 (Mboat7Δhep) 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. Mboat7Δhep 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 Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered LPI and phosphatidylinositol subspecies in Mboat7Δhep 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.



Publication History

Article published online:
07 September 2021

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