Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice

• Main Authors: Matteo Tardelli, Francesca V. Bruschi, Claudia D. Fuchs, Thierry Claudel, Nicole Auer, Victoria Kunczer, Onne A. H. O. Ronda, Henkjan J. Verkade, Tatjana Stojakovic, Hubert Scharnagl, Michael Trauner
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: International Journal of Molecular Sciences
• Subjects: NAFLD; MGL; PNPLA3; NASH; inflammation
• Online Access: https://www.mdpi.com/1422-0067/22/4/2126
• ISSN: 1661-6596; 1422-0067

Altered lipid metabolic pathways including hydrolysis of triglycerides are key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether adiponutrin (patatin-like phospholipase domain containing protein-3—PNPLA3) and monoacylglycerol lipase (MGL) synergistically contribute to disease progression remains unclear. We generated double knockout (<i>DKO</i>) mice lacking both <i>Mgl</i> and <i>Pnpla3</i>; <i>DKO</i> mice were compared to <i>Mgl^−/−</i> after a challenge by high-fat diet (HFD) for 12 weeks to induce steatosis. Serum biochemistry, liver transaminases as well as histology were analyzed. Fatty acid (FA) profiling was assessed in liver and adipose tissue by gas chromatography. Markers of inflammation and lipid metabolism were analyzed. Bone marrow derived macrophages (BMDMs) were isolated and treated with oleic acid. Combined deficiency of <i>Mgl</i> and <i>Pnpla3</i> resulted in weight gain on a chow diet; when challenged by HFD, <i>DKO</i> mice showed increased hepatic FA synthesis and diminished beta-oxidation compared to <i>Mgl^−/−.</i><i>DKO</i> mice exhibited more pronounced hepatic steatosis with inflammation and recruitment of immune cells to the liver associated with accumulation of saturated FAs. Primary BMDMs isolated from the <i>DKO</i> mice showed increased inflammatory activities, which could be reversed by oleic acid supplementation. <i>Pnpla3</i> deficiency aggravates the effects of <i>Mgl</i> deletion on steatosis and inflammation in the liver under HFD challenge.