Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58

Abstract

Background:The role of CGI-58 in muscle triacylglycerol catabolism is unknown. The presence of CGI-58 increases the lipolytic activity of adipose triglyceride lipase (ATGL). Results: Muscle-specific CGI-58 deficiency causes muscle steatosis and cardiac dysfunction despite elevated ATGL protein expression. Conclusion: Muscle lipolysis critically depends on both CGI-58 and ATGL. Significance: Muscle CGI-58 deficiency provokes severe cardiac steatosis and dysfunction.

Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis

“…Furthermore, the expression of PPAR ␣ (and ␤ / ␦ ) target genes involved in mitochondrial FAO was moderately but signifi cantly reduced, which could be a consequence of impaired lipolysis, as has been reported for mice lacking ATGL or CGI-58 specifi cally in muscle ( 15,16 ). The observation that CM-Fgf21 mice exhibit normal heart function suggests that in these animals mitochondrial FAO is more moderately affected as compared with the marked defect in mitochondrial FAO and cardiac function of ATGL-defi cient mice.…”

“…This assumption is further supported by the strong induction of FGF21 expression in differentiated H9C2 cardiomyotubes when treated with ER stress-activating agents including DTT, tunicamycin, and palmitate. Mice lacking the ATGL coactivator CGI-58 in CM (and skeletal muscle) ( 15 ) show a similar increase in cardiac FGF21 expression.…”

“…Mice expressing ATGL solely in CM were generated by breeding the ATGL transgene onto an ATGL-defi cient background ( 16 ). Mice with muscle-specifi c CGI-58 disruption and transgenic mice overexpressing Perlipin 5 in the heart were generated as previously described ( 15,20 ). The PPAR ␣ agonist Wy14,643 (Cayman Chemical Co., Ann Arbor, MI) was provided via ad libitum feeding a chow diet containing 0.1% Wy14,643 for 2 weeks.…”

Deficiency of a Lipid Droplet Protein, Perilipin 5, Suppresses Myocardial Lipid Accumulation, Thereby Preventing Type 1 Diabetes-Induced Heart Malfunction

“…It was also reported that LDs supply lipid ligands, FAs and their metabolites, for PPAR␣ activation through lipolysis (22,(36)(37)(38). In the hearts of diabetic Plin5 Ϫ/Ϫ mice, LDs were not detectable, and the intramyocardial FA levels were lower than those of diabetic WT mice.…”

“…Hence, abnormal lipid metabolism, including aberrant lipid accumulation, is regarded as an important pathogenesis of diabetic cardiomyopathy. Efforts have been made to elucidate the link between lipid metabolism and heart performance using obese and diabetic mouse models as well as genetically modified mice (16)(17)(18)(19)(20)(21)(22)(23)(24). Previous studies focusing on abnormal lipid metabolism suggest two causes for major pathogenesis of diabetes-induced heart malfunction.…”