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Role of Hepatic PLIN2 and PLIN4 in The Development of Western Type Diet Induced Hepatosteatosis

Nonalcoholic fatty liver disease (NAFLD) is characterized by the excessive accumulation of triglyceride (TAG) in the liver. In hepatocytes TAG is stored intracellularly within cytoplasmic lipid droplets (LD). Intracellular LD are coated with various LD associated proteins in the perilipin (PLIN) and FSP27 family. These LD associated proteins are thought to promote LD formation by regulating the hydrolysis of stored TAG. Hepatocyte‐specific knockout of the LD‐associated protein perilipin 2 (PLIN2) protects mice from developing NAFLD and associated inflammation when fed a methionine‐choline deficient diet for 15 days, indicating an essential role for PLIN2 in the development of fatty liver disease. However, the protective effects of hepatocyte‐specific knockout of PLIN2 on hepatic steatosis in mice fed a high fat, western diet (WTD) are unknown. To determine the function of hepatic PLIN2 in the development of WTD‐induced liver steatosis, 16 week old hepatocyte‐specific PLIN2 knockout mice (PLIN2Alb‐Cre) and floxed controls (PLIN2fl/fl) were fed either a WTD previously shown to induce significant hepatosteatosis, or a low fat control diet (LFD). 20 weeks of WTD (44% fat, 39% carbohydrate, 34% sucrose by weight) feeding significantly increased weight gain (14.9g WTD vs. 1.6g LFD, p<0.001), reduced insulin sensitivity as measured by intraperitoneal (IP) insulin tolerance test (AUC increased 56% vs LFD, p<0.05), impaired glucose tolerance as measured by IP glucose tolerance test (AUC increased 59% vs LFD p<0.05) and increased accumulation of hepatic TAG (10.6ug/mg WTD vs 67.3ug/mg LFD, p<0.01). Surprisingly, the absence of hepatocyte PLIN2 expression did not prevent liver steatosis in mice fed a WTD. Interestingly, hepatocyte‐specific knockout of PLIN2 reduced the accumulation of liver triglycerides following LFD feeding (3.3ug/mg PLIN2Alb‐Cre vs. 8.1ug/mg PLIN2fl/fl). To determine whether other LD‐associated proteins may compensate for the absence of PLIN2 we measured the expression of PLIN1, PLIN3, PLIN4, and FSP27. PLIN4 was the only LD‐associated protein affected by either diet or genotype, significantly upregulated by WTD feeding in both lines of mice (increased 4.1 fold vs. LFD). At the present time there are no studies on the role of PLIN4 in the development of hepatic steatosis. We hypothesize that during LFD feeding PLIN2 is necessary for hepatic TAG storage. However, during WTD feeding we hypothesize that PLIN4 is a critical determinant of liver TAG accumulation. Future experiments using newly developed anti‐sense oligonucleotides directed against PLIN4 are underway to determine the relative contribution of PLIN4 to hepatic TAG storage during WTD feeding.