Research Project
Grant-in-Aid for Scientific Research (C)
Study 1: Function of hormone-sensitive lipase in diabetic cardiomyopathyWe sought to explore a pathophysiological function of cardiac HSL in the development of diabetic cardiomyopathy. Transgenic (Tg) mice with heart-specific HSL-overexpression were generated and hearts were analyzed after induction of diabetes by streptozotocin. Electron microscopy showed numerous lipid droplets in wildtype (Wt) hearts after 3 weeks of diabetes, whereas Tg mice showed no lipid droplet accumulation. Cardiac lipid peroxide content was 2-fold lower in Tg hearts than Wt hearts. The mRNA expressions for PPARα, genes for triacylglycerol synthesis were increased with diabetes in Wt hearts, whereas this induction was absent in Tg hearts. Diabetic Wt hearts showed interstitial fibrosis. Since HSL-overexpression inhibits cardiac steatosis and fibrosis by apparently hydrolyzing toxic lipid metabolites, cardiac HSL could be a therapeutic target for regulating diabetic cardiomyopathy.Study 2: Function of hormone-sensitive lipase in cardiac energy metabolismWe investigated how disruption of HSL affects cardiac energy metabolism in response to fasting and refeeding. HSL-KO mice and wildtype (Wt) littermates were fasted for 24 h followed by-6h of refeeding to study cardiac metabolism. Plasma FA concentration in Wt mice was elevated 2-fold with fasting, while KO mice lacked this elevation. Cardiac FA uptake was 2-fold lower in KO mice than Wt mice during fasting. Cardiac VLDL uptake and lipoprotein lipase (LPL) activity was 2-fold higher in KO mice during fasting. The KO hearts showed undetectable activity of neutral cholesteryl esterase and 40% lower non-LPL triglyceride lipase activity in refed conditions, and overt steatosis. Adipose and cardiac HSL coordinately control cardiac energy metabolism to maintain normal cardiac function and steatosis in response to altering food availability.
All 2008 2007 2006 2005 Other
All Journal Article (8 results) (of which Peer Reviewed: 4 results) Presentation (12 results)
Am J Physiol Endocrinol Metab 294(in press)
Biochem Biophys Res Commun 368
Pages: 716-722
Endocrinology 146
Pages: 3286-3294
J Mol Cell Cardiol 38
Pages: 637-646
Am J Physiol Endocrinol Metab (in press)
