Obesity-linked suppression of membrane-bound O -acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease

• Published in: eLife Vol. 8
• Main Authors: Helsley, Robert N, Varadharajan, Venkateshwari, Brown, Amanda L, Gromovsky, Anthony D, Schugar, Rebecca C, Ramachandiran, Iyappan, Fung, Kevin, Kabbany, Mohammad Nasser, Banerjee, Rakhee, Neumann, Chase K, Finney, Chelsea, Pathak, Preeti, Orabi, Danny, Osborn, Lucas J, Massey, William, Zhang, Renliang, Kadam, Anagha, Sansbury, Brian E, Pan, Calvin, Sacks, Jessica, Lee, Richard G, Crooke, Rosanne M, Graham, Mark J, Lemieux, Madeleine E, Gogonea, Valentin, Kirwan, John P, Allende, Daniela S, Civelek, Mete, Fox, Paul L, Rudel, Lawrence L, Lusis, Aldons J, Spite, Matthew, Brown, J Mark
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 17.10.2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Acylation; Acyltransferase; Acyltransferases - genetics; Analysis; Animals; Biopsy; Cirrhosis; Consortia; Development and progression; Disease Progression; Fatty acids; Fatty liver; Fibrosis; Gastrointestinal surgery; Genes; Genetic diversity; Genetic research; Genetics; Hepatitis; hepatology; High fat diet; Human Biology and Medicine; Humans; Inflammation; Lipids; Liver cirrhosis; Liver diseases; Medicine; Membrane Proteins - genetics; Mice; Microscopy; NAFLD; Non-alcoholic Fatty Liver Disease - genetics; Novels; Obesity; Obesity - genetics; Physiological aspects; Quantitative genetics; Quantitative trait loci; Software; Statistical analysis; Transcription; triacylglycerol; Variance analysis; Viral hepatitis; Virus diseases; California; Canada; Los Angeles California; United States > US; human biology; hepatology; mouse; NAFLD; medicine; triacylglycerol
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.49882

Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound -acyltransferase domain-containing 7 ( ) and transmembrane channel-like 4 ( ) 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 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 loss, but not , in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet. 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 -dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of NAFLD.