Abstract

Perilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Mice with or without whole-body deletion of perilipin-2 (Plin2-null) were fed either Western or control diets for 30 weeks. Perilipin-2 deletion prevents obesity and insulin resistance in Western diet-fed mice and dramatically reduces hepatic triglyceride and cholesterol levels in mice fed Western or control diets. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. GC-MS lipidomics demonstrate that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. To examine the possibility that lipidomic actions of PLIN2 deletion contribute to suppression of SREBP activation, we isolated endoplasmic reticulum membrane fractions from long-term Western diet-fed wild type (WT) and Plin2-null mice. Lipidomic analyses reveal that endoplasmic reticulum membranes from Plin2-null mice are markedly enriched in ω-3 and ω-6 long-chain polyunsaturated fatty acids, which others have shown inhibit SREBP activation and de novo lipogenesis. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease.

Highlights

  • Perilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease

  • We had expected a reduction in total neuisome proliferator-activated receptor; LC, long chain; P/T, phospho/total; spliced XBP1 (sXBP1), spliced Xbp1; unspliced XBP1 (uXBP1), unspliced Xbp1; DHA, docosahexaenoic acid; ROS, reactive oxygen species; FXR, farnesoid X receptor; LXR, liver X receptor; FAME, fatty acid methyl ester; SREBP, sterol regulatory element-binding protein; ChREBP, carbohydrate-response element-binding protein; ACC, acetyl-CoA carboxylase; AMPK,5Ј-AMP-activated protein kinase; TG, triglyceride

  • Body weights of Western diet (WD)-fed wild type (WT) mice doubled over 30 weeks, whereas body weights of CD-fed WT mice increased by 43% (Fig. 1A), and body weights of Western and control diet-fed Plin2-null animals increased by 16 and 31%, respectively

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Summary

Edited by George Carman

Perilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease. We previously generated mice with whole-body knock-out of PLIN2 (Plin2-null) [13] These animals are resistant to obesity, adipose tissue inflammation, and liver steatosis (NAFLD) when raised on a high fat diet. Using Plin2-null mice on Western (WD) or control (CD) diets for 30 weeks, we show that loss of Plin prevents diet-induced steatosis largely by impairing activation of the SREBP-1 and SREBP-2 pathways through effects on membrane lipid composition. The findings of this study further our understanding of the role of PLIN2 in diet-induced fatty liver formation and provide evidence of its function in coordinating content and composition of biologically active cellular lipids in the liver

Results
Discussion
Experimental Procedures

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