Loss of hepatic Mboat7 leads to liver fibrosis in an inflammation-independent manner

Background & Aims:

Human association studies have identified association of the rs641738 C>T variant in membrane-bound O-acyltransferase domain containing 7 (MBOAT7) with non-alcoholic fatty liver disease (NAFLD). We aim to better understand the mechanism by which the rs641738 variant contributes to the pathogenesis of NAFLD.

Methods:

Mice with hepatocyte-specific deletion of Mboat7 (Mboat7Δhep) were generated and livers characterized by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analyzed the association of the rs641738 genotype with liver inflammation and fibrosis in 361 NAFLD patients and obtained genotype-specific liver lipidomes from 336 human biopsies.

Results:

Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterized by increased hepatic cholesterol ester content after 10 weeks on a chow diet. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirus staining (p < 0.05) and hydroxyproline content (p < 0.05) while the inflammatory cell populations and inflammatory mediators were not changed. In a human biopsied NAFLD cohort, MBOAT7 rs641738T 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 (LPI) levels. The remodeling of LPI and phosphatidylinositol subspecies patterns in Mboat7Δhep livers and humans rs641738 TT carriers were similar.

Conclusion:

Mboat7 deficiency in mice and human points to an inflammation-independent pathway to liver fibrosis, that may be mediated by lipid signalling and represents a potentially targetable treatment option in NAFLD.