Cardiac overexpression of perilipin 2 induces dynamic steatosis: prevention by hormone-sensitive lipase

Abstract

Cardiac intracellular lipid accumulation (steatosis) is a pathophysiological phenomenon observed in starvation and diabetes mellitus. Perilipin 2 (PLIN2) is a lipid droplet (LD)-associated protein expressed in nonadipose tissues, including the heart. To explore the pathophysiological function of myocardial PLIN2, we generated transgenic (Tg) mice by cardiac-specific overexpression of PLIN2. Tg hearts showed accumulation of numerous small LDs associated with mitochondrial chains and high cardiac triacylglycerol (TAG) content [8-fold greater than wild-type (WT) mice]. Despite massive steatosis, cardiac uptake of glucose, fatty acids and VLDL, systolic function, and expression of metabolic genes were comparable in the two genotypes, and no morphological changes were observed by electron microscopy in the Tg hearts. Twenty-four hours of fasting markedly reduced steatosis in Tg hearts, whereas WT mice showed accumulation of LDs. Although activity of adipose triglyceride lipase in heart homogenate was comparable between WT and Tg mice, activity of hormone-sensitive lipase (HSL) was 40-50% less in Tg than WT mice under both feeding and fasting conditions, suggesting interference of PLIN2 with HSL. Mice generated through crossing of PLIN2-Tg mice and HSL-Tg mice showed cardiac-specific HSL overexpression and complete lack of steatosis. The results suggest that cardiac PLIN2 plays an important pathophysiological role in the development of dynamic steatosis and that the latter was prevented by upregulation of intracellular lipases, including HSL.

Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation

“…It may be that the energetic needs of an E4 astrocyte in the absence of robust glucose metabolism overpower the inhibitory effect of PLIN2 on LD lipolysis. The overexpression of PLIN2 has also been shown to increase LD formation in various cell types [46,47,48]. This is congruent with our findings in regards to E4 astrocytes, where an increase in LD number paralleled with increased PLIN2 expression.…”

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…123 It has reportedly been demonstrated that overexpression of PLIN2 is sufficient to increase lipid droplet formation, while the downregulation of PLIN2 reduces lipid droplet formation in a wide range of cells, indicating that PLIN2 can actively determine lipid droplet pool size. 123,135,136 PLIN2 protein levels closely correlate with cellular triglyceride contents in beta cells as well. 123,135,136 PLIN2 protein levels closely correlate with cellular triglyceride contents in beta cells as well.…”

“…123 In nonbeta cells, the modulation of PLIN2 expression is reported to affect multiple aspects of cellular lipid handling, including FA uptake, beta-oxidation, and activation of nuclear receptors in the liver, heart, macrophages, and white adipocytes. 123,135,136 PLIN2 protein levels closely correlate with cellular triglyceride contents in beta cells as well. PLIN2 protein is increased in beta cell lines, mouse islets, and human islets after fatty acid loading in vitro and in islets from obese mice (high-fat diet, ob/ob mice) and fasted mice.…”

Proteomic Analysis of Myocardia Containing the Obscurin R4344Q Mutation Linked to Hypertrophic Cardiomyopathy

“…The expression levels of three proteins involved in the transport of long chain fatty acids are altered, too, including glutamic-oxaloacetic transaminase 2 (Got2), perilipin 2 (Plin2), and solute carrier family 27 (Table 4). Got2 and Plin2 upregulation in the heart has been shown to lead to accumulation of lipid droplets (Holloway et al, 2011;Ueno et al, 2017). Interestingly, the expression levels of solute carrier family 27 have been suggested to positively correlate with fatty acid uptake (Milger et al, 2006), but also lipid oxidation (Jeppesen et al, 2012).…”