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J Biol Chem. 2016 Nov 11;291(46):24231-24246. Epub 2016 Sep 27.

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome.

Author information

1
From the Integrated Physiology Graduate Program.
2
Division of Reproductive Sciences, and.
3
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
4
From the Integrated Physiology Graduate Program, jim.mcmanaman@ucdenver.edu.

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.

KEYWORDS:

endoplasmic reticulum stress (ER stress); gene knockout; lipid droplet; lipid metabolism; lipogenesis; liver metabolism; mass spectrometry (MS); membrane lipid; metabolic disease; perilipin-2

PMID:
27679530
PMCID:
PMC5104945
DOI:
10.1074/jbc.M116.759795
[Indexed for MEDLINE]
Free PMC Article

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