Perilipin 5 Deletion in Hepatocytes Remodels Lipid Metabolism and Causes Hepatic Insulin Resistance in Mice

Stacey N. Keenan, Ruth C. Meex, Jennifer C. Y. Lo, Andrew Ryan, Shuai Nie, Magdalene K. Montgomery, Matthew J. Watt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

37 Citations (Web of Science)

Abstract

Defects in hepatic lipid metabolism cause nonalcoholic fatty liver disease and insulin resistance, and these pathologies are closely linked. Regulation of lipid droplet metabolism is central to the control of intracellular fatty acid fluxes, and perilipin 5 (PLIN5) is important in this process. We examined the role of PLIN5 on hepatic lipid metabolism and systemic glycemic control using liver-specific Pliny-deficient mice (Plin5(LKO)). Hepatocytes isolated from Plin5(LKO) mice exhibited marked changes in lipid metabolism characterized by decreased fatty acid uptake and storage, decreased fatty acid oxidation that was associated with reduced contact between lipid droplets and mitochondria, and reduced triglyceride secretion. With consumption of a high-fat diet, Plin5(LKO)) mice accumulated intrahepatic triglyceride, without significant changes in inflammation, ceramide or diglyceride contents, endoplasmic reticulum stress, or autophagy. Instead, livers of Plin5(LKO)) mice exhibited activation of c-Jun N-terminal kinase, impaired insulin signal transduction, and insulin resistance, which impaired systemic insulin action and glycemic control. Re-expression of Plin5 in the livers of Plin5(LKO)) mice reversed these effects. Together, we show that Plin5 is an important modulator of intrahepatic lipid metabolism and suggest that the increased Plin5 expression that occurs with overnutrition may play an important role in preventing hepatic insulin resistance.

Original languageEnglish
Pages (from-to)543-555
Number of pages13
JournalDiabetes
Volume68
Issue number3
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • ADIPOSE TRIACYLGLYCEROL LIPASE
  • HIGH-FAT DIET
  • SKELETAL-MUSCLE
  • PROTEIN
  • EXPRESSION
  • EXERCISE
  • SENSITIVITY
  • HOMEOSTASIS
  • ACID
  • JNK

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