Abstract
Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound O-acyltransferase domain-containing 7 (MBOAT7) and transmembrane channel-like 4 (TMC4) 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 MBOAT7 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 Mboat7 loss, but not Tmc4, in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet. Mboat7 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 Mboat7-dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition that affects roughly one-third of adults in the United States (Cohen et al, 2011; Machado and Diehl, 2016; Rinella and Sanyal, 2016; Wree et al, 2013)
We found that hepatic membrane bound O-acyltransferase domain-containing 7 (MBOAT7) expression was dramatically reduced in obese people, when compared to normal weight controls (Figure 1A)
Given the fact that the rs641738 polymorphism is located in exon 1 of the transmembrane channellike 4 (TMC4) gene, and we unexpectedly found that Mboat7 antisense oligonucleotides (ASOs) treatment reduces transmembrane channel-like gene family 4 (Tmc4) expression (Figure 3B,E), we wanted to examine whether alteration in Tmc4 may be a key regulator of hepatic steatosis
Summary
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition that affects roughly one-third of adults in the United States (Cohen et al, 2011; Machado and Diehl, 2016; Rinella and Sanyal, 2016; Wree et al, 2013). Helsley et al grew human liver cells in the laboratory and lowered their levels of MBOAT7, which led to excess fat accumulating in the cells This increase in fat accumulation was, at least in part, due to how these cells metabolize fats when MBOAT7 is reduced: they start making more new fats and consume fewer lipids to produce energy. These findings provide a link between obesity and liver damage in both humans and mice, and show how a decrease in MBOAT7 levels causes changes in fat metabolism that could lead to NAFLD.
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