title: Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice.
abstract: Intracellular lipid accumulation (steatosis) and resultant lipotoxicity are key features of diabetic cardiomyopathy. Since cardiac hormone-sensitive lipase (HSL) is activated in diabetic mice, we 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 cardiac histology, function, lipid profile, and gene expressions were analyzed after induction of diabetes by streptozotocin. Electron microscopy showed numerous lipid droplets in wild-type (Wt) hearts after 3 wk of diabetes, whereas Tg mice showed no lipid droplet accumulation. Cardiac content of acylglycerides was increased approximately 50% with diabetes in Wt mice, whereas this was blunted in Tg hearts. Cardiac lipid peroxide content was twofold lower in Tg hearts than in Wt hearts. The mRNA expressions for peroxisome proliferator-activated receptor-alpha, genes for triacylglycerol synthesis, and lipoprotein lipase were increased with diabetes in Wt hearts, whereas this induction was absent in Tg hearts. Expression of genes associated with lipoapoptosis was decreased, whereas antioxidant protein metallothioneins were increased in diabetic Tg hearts. Diabetic Wt hearts showed interstitial fibrosis and increased collagen content. However, Tg hearts displayed no overt fibrosis, concomitant with decreased expression of collagens, transforming growth factor-beta, and matrix metalloproteinase 2. Notably, mortality during the experimental period was approximately twofold lower in diabetic Tg mice compared with Wt mice. In conclusion, 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.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medical Science, University of Fukui, Fukui, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ueno
authors.forename: Jinya
authors.initials: J
authors.lastname: Suzuki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Zenimaru
authors.forename: Sadao
authors.initials: S
authors.lastname: Takahashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Koizumi
authors.forename: Sakon
authors.initials: S
authors.lastname: Noriki
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Shen
authors.forename: Fredric B
authors.initials: FB
authors.lastname: Kraemer
authors.forename: Isamu
authors.initials: I
authors.lastname: Miyamori
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D009202:Cardiomyopathies / Q000201:enzymology* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005355:Fibrosis / Q000201:enzymology; D007328:Insulin / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002787:Sterol Esterase / Q000096:biosynthesis* / Q000235:genetics; D014280:Triglycerides / Q000097:blood / Q000235:genetics
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D047493:PPAR alpha; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; D002787:Sterol Esterase; D008071:Lipoprotein Lipase