Obesity-linked suppression of membrane-bound <i>O</i>-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease.

Abstract

Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound <i>O</i>-acyltransferase domain-containing 7 (<i>MBOAT7</i>) and transmembrane channel-like 4 (<i>TMC4</i>) that associate with increased risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related cirrhosis, and liver fibrosis in those infected with viral hepatitis (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017). Based on hepatic expression quantitative trait loci analysis, it has been suggested that <i>MBOAT7</i> loss of function promotes liver disease progression (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017), but this has never been formally tested. Here we show that <i>Mboat7</i> loss, but not <i>Tmc4</i>, in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet. <i>Mboat7</i> loss of function is associated with accumulation of its substrate lysophosphatidylinositol (LPI) lipids, and direct administration of LPI promotes hepatic inflammatory and fibrotic transcriptional changes in an <i>Mboat7</i>-dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of NAFLD.