Low cardiac lipolysis reduces mitochondrial fission and prevents lipotoxic heart dysfunction in Perilipin 5 mutant mice

Abstract

Aims Lipotoxic cardiomyopathy in diabetic and obese patients typically encompasses increased cardiac fatty acid (FA) uptake eventually surpassing the mitochondrial oxidative capacity. Lowering FA utilization via inhibition of lipolysis represents a strategy to counteract the development of lipotoxic heart dysfunction. However, defective cardiac triacylglycerol (TAG) catabolism and FA oxidation in humans (and mice) carrying mutated ATGL alleles provokes lipotoxic heart dysfunction questioning a therapeutic approach to decrease cardiac lipolysis. Interestingly, decreased lipolysis via cardiac overexpression of Perilipin 5 (Plin5), a binding partner of ATGL, is compatible with normal heart function and lifespan despite massive cardiac lipid accumulation. Herein, we decipher mechanisms that protect Plin5 transgenic mice from the development of heart dysfunction. Methods and results We generated mice with cardiac-specific overexpression of Plin5 encoding a serine-155 to alanine exchange (Plin5-S155A) of the protein kinase A phosphorylation site, which has been suggested as a prerequisite to stimulate lipolysis and may play a crucial role in the preservation of heart function. Plin5-S155A mice showed a substantial increase in cardiac TAG and ceramide levels, which was comparable to mice overexpressing non-mutated Plin5. Lipid accumulation was compatible with normal heart function even under mild stress. Plin5-S155A mice showed reduced cardiac FA oxidation but normal ATP production and changes in the Plin5-S155A phosphoproteome compared to Plin5 transgenic mice. Interestingly, mitochondrial recruitment of dynamin-related protein 1 (Drp1) was markedly reduced in cardiac muscle of Plin5-S155A and Plin5 transgenic mice accompanied by decreased phosphorylation of mitochondrial fission factor, a mitochondrial receptor of Drp1. Conclusions This study suggests that low cardiac lipolysis is associated with reduced mitochondrial fission and may represent a strategy to combat the development of lipotoxic heart dysfunction.

The Role of Adipose Triglyceride Lipase and Cytosolic Lipolysis in Cardiac Function and Heart Failure

“… 41 In addition, recently, PLIN5 has been shown to protect mitochondrial function via the reduction of mitochondrial fission. 111 Consistent with the proposed barrier function, the constitutive deletion of PLIN5 strongly reduced cardiac TAG content. PLIN5 deficiency resulted in a significant reduction in systolic LV function under dobutamine stress.…”

“… 51 Mitochondrial respiration was maintained or only mildly impaired in PLIN5-overexpressing cardiomyocytes compared to a stronger defect in ATGL-deficient hearts. 28 , 41 , 111 The differences in cardiac function between PLIN5 transgenic- and ATGL-deficient hearts in the presence of similar cardiac TAG accumulation have been explained by the induction of the antioxidative pathway mediated by nuclear factor-E2-related factor 2 in PLIN5 mice. 41 In addition, recently, PLIN5 has been shown to protect mitochondrial function via the reduction of mitochondrial fission.…”

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…Studies conducted utilizing the hyperinsulinemic-euglycemic clamp technique in muscle biopsies have shown that subjects exposed to high fatty acid infusions reduce glucose oxidation, intramuscular concentration of glucose 6-phosphate, glycogen synthesis, and translocation of GLUT4 [37]. Chronic positive diet energy balance (mainly carbohydrates and saturated NEFA), increased de novo lipogenesis, and peripheral lipolysis are among the main causes favoring the ectopic accumulation of fatty acids [38][39][40].…”

The Gene and Protein Expression of the Main Components of the Lipolytic System in Human Myocardium and Heart Perivascular Adipose Tissue. Effect of Coronary Atherosclerosis

“…It is well known that fatty acids are the principal energy fuel of the heart. Increased TG deposition in the myocardium can result from increased fatty acid (FA) uptake or decreased FA oxidation [37]. Recently cardiomyocytes TG depot has been identified as a dynamic source of LCFA utilized mainly for mitochondrial energy production via beta-oxidation and the citric acid cycle [6].…”