Robert N Helsley 1 , 2 , Venkateshwari Varadharajan 1 , Amanda L Brown 1 , Anthony D Gromovsky 1 , Rebecca C Schugar 1 , Iyappan Ramachandiran 1 , Kevin Fung 1 , Mohammad Nasser Kabbany 1 , Rakhee Banerjee 1 , Chase K Neumann 1 , Chelsea Finney 1 , Preeti Pathak 1 , Danny Orabi 1 , Lucas J Osborn 1 , William Massey 1 , Renliang Zhang 1 , Anagha Kadam 1 , Brian E Sansbury 3 , Calvin Pan 4 , 5 , 6 , Jessica Sacks 7 , Richard G Lee 8 , Rosanne M Crooke 8 , Mark J Graham 8 , Madeleine E Lemieux 9 , Valentin Gogonea 10 , John P Kirwan 7 , Daniela S Allende 11 , Mete Civelek 12 , Paul L Fox 1 , Lawrence L Rudel 13 , Aldons J Lusis 4 , 5 , 6 , Matthew Spite 3 , J Mark Brown , 1
17 October 2019
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.
Non-alcoholic fatty liver disease, or NAFLD for short, is a medical condition that develops when the liver accumulates excess fat. It can lead to complications such as diabetes and liver scarring. In humans, mutations that inactivate a protein called MBOAT7 increase the risk of fat accumulating in the liver.
Genetic studies suggest that low levels of MBOAT7 in a human’s liver cells increase the severity of NAFLD. Yet the links between MBOAT7, NAFLD and obesity are not well understood. Helsley et al. used data from humans and from obese mice that had been fed a high-fat diet to investigate the relationship between NAFLD and MBOAT7. This revealed that people who are obese have lower levels of MBOAT7 in their livers. Next, obese mice were genetically manipulated to produce less MBOAT7, which led them to develop more severe NAFLD.
Helsley et al. then 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. The results could drive new approaches to treating liver damage in patients with mutations in the gene that codes for MBOAT7.