title: Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice.
abstract: Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2'-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Inoue
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Inoguchi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sonoda
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hirata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D000818:Animals; D058065:Diabetic Cardiomyopathies / Q000378:metabolism*; D015536:Down-Regulation; D008049:Lipase / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D014018:Tissue Distribution; D000217:Acyltransferases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D008049:Lipase; C492986:Abhd5 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: Adipose triglyceride lipase; Comparative gene identification-58; Diabetic cardiomyopathy; Myocardial steatosis; Protein kinase C