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.
- liver fibrosis, lipidomics
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JH and PS are joint senior authors.
Contributors Project was conceived and experiments were conceptualised by: VRT, PS, MB, EK, TC, FS, MMS, and JH. Experiments were performed by VRT, PS, OK, EP, OV, KH, MN, SN, AD, DRR and MVB. Patient sample collection and coordination was done by CS, WVS, SH, AH, TB, EA, CD and CR. Data analysis was done by VRT, PS, SB, AH, JAHW, JKP and JMA. Manuscript was written and edited by VRT, PS, JH, TC, AS, SZ and FS.
Funding This study was supported by the German Ministry of Research and Education (BmBF) through the Liver Systems Medicine (LiSyM) network grant (to JH and AS) and ERACOSysMed (Dynaflow) grant (to JH), an ERC grant (DEMETINL to TC) and Lipidomics and Informatics for Life Sciences (LIFS) grant Unit of the de. NBI Consortium (AS). Additional support came from the Swiss National Funds (grants 310030_138747/1 and 310030_169196 to F.S.) Contributions by JP were partly funded by the Bavarian State Ministry of Science and the Arts in the framework of the Centre Digitisation. Bavaria (ZDB).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval Subjects recruited for the genetic association study came from different sites, at which the study protocol was approved by the ethics committees of the participating institutions.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Not applicable.
Author note The transciptomic data is available at GEO under id GSE139992
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