Abstract
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 (DKO) mice lacking both Mgl and Pnpla3; DKO mice were compared to Mgl−/− 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 Mgl and Pnpla3 resulted in weight gain on a chow diet; when challenged by HFD, DKO mice showed increased hepatic FA synthesis and diminished beta-oxidation compared to Mgl−/−. DKO 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 DKO mice showed increased inflammatory activities, which could be reversed by oleic acid supplementation. Pnpla3 deficiency aggravates the effects of Mgl deletion on steatosis and inflammation in the liver under HFD challenge.
Highlights
To study whether loss of both Mgl and Pnpla3, as key intracellular lipases involved in hydrolysis of stored fat, would impact lipid partitioning and regulation of nuclear receptor (NR) signaling, we first characterized a double knockout (DKO) mouse model at baseline
We discovered that Pnpla3 is involved in inflammation and lipid accumulation of different species of Fatty acid (FA) in an nonalcoholic fatty liver disease (NAFLD) mouse model
This contrasted to the minimal inflammation, diminished body weight and steatosis seen in Mgl−/− animals on the same diet [20,21], which is usually not expected to trigger steatohepatitis [24] in contrast to other established models such as methionine-choline deficient diet [24]
Summary
The genetic polymorphism rs738409 in patatin-like phospholipase domain containing protein-3 (PNPLA3) was shown to confer susceptibility to NAFLD in a genome-wide association scan of nonsynonymous sequence variations [9]. This polymorphism encodes for an isoleucine to methionine substitution at position 148, impairing the enzymatic, putative lipolytic function of adiponutrin [10]. Despite the strong association of PNPLA3 with human NAFLD/NASH and other liver disease, Pnpla3−/− mice showed no phenotype, including differences in TG hydrolysis, energy/glucose/lipid homoeostasis or hepatic steatosis/injury after high-fat diet (HFD) challenge [10]. We found that the concomitant deficiency of Pnpla and Mgl causes complex changes in FA metabolism and aggravates steatosis and inflammation
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