Perilipins: Protectors of lipid reservoirs: Regulation of lipid droplets and lipid flux by Plin2 and Plin5

Abstract

Lipid droplets are organelles that store neutral lipids. Many metabolic disorders are associated with altered lipid droplet storage. Proteins of the Plin family regulate lipid droplet stability and are potential therapeutic targets of metabolic diseases. The goal of the thesis was to study the role of Plin2 and Plin5 for lipid droplet storage in non-adipocytes. We applied histological, molecular and isotope labelling methods to characterize cells and organs of mice lacking Plin2 or Plin5. Our analyses focused on lipid droplet storage, cellular fatty acid flux, energy metabolism and cholesterol balance. Plin2 protected lipid droplets against lipolysis in myotubes. Increased fatty acid release from lipid droplets in Plin2-null myotubes led to decreased triacylglycerol storage, increased fatty acid oxidation and repressed glucose utilization. Altered expression of transcription factors contributed to this redirected metabolism. Plin2-null adrenals were enlarged with increased content of cholesteryl ester-rich lipid droplets. The secretion of corticosterone was normal. Analysis of gene expression suggests that cellular cholesterol balance was disturbed and cholesterol efflux was activated. Ceroid-like structures, multilamellar bodies and phosphatidylglycerol accumulated in adrenals, indicative of disturbed lysosomal activity. Plin5 protected cardiac lipid droplets by repressing lipolysis. Plin5-null cardiomyocytes accumulated fatty acid-derived intermediate metabolites but had normal fatty acid oxidation rate. Plin5-null cardiomyocytes treated with oleic acids stored more glycogen and had increased tolerance to hypoxia. Plin5 deficiency led to cardiac remodeling with age. In sum, Plin2 and Plin5 protects intracellular reservoirs of esterified fatty acids and cholesterol against lipolytic activity. Removal of Plin2 or Plin5 affects lipid droplet storage, with secondary effects on e.g. intracellular fatty acid flux, energy metabolism and cholesterol balance.