title: β-Lapachone ameliorates lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice.
abstract: Lipotoxic cardiomyopathy is caused by myocardial lipid accumulation and often occurs in patients with diabetes and obesity. This study investigated the effects of β-lapachone (β-lap), a natural compound that activates Sirt1 through elevation of the intracellular NAD+ level, on acyl CoA synthase (ACS) transgenic (Tg) mice, which have lipotoxic cardiomyopathy. Oral administration of β-lap to ACS Tg mice significantly attenuated heart failure and inhibited myocardial accumulation of triacylglycerol. Electron microscopy and measurement of mitochondrial complex II protein and mitochondrial DNA revealed that administration of β-lap restored mitochondrial integrity and biogenesis in ACS Tg hearts. Accordingly, β-lap administration significantly increased the expression of genes associated with mitochondrial biogenesis and fatty acid metabolism that were down-regulated in ACS Tg hearts. β-lap also restored the activities of Sirt1 and AMP-activated protein kinase (AMPK), the two key regulators of metabolism, which were suppressed in ACS Tg hearts. In H9C2 cells, β-lap-mediated elevation of AMPK activity was retarded when the level of Sirt1 was reduced by transfection of siRNA against Sirt1. Taken together, these results indicate that β-lap exerts cardioprotective effects against cardiac lipotoxicity through the activation of Sirt1 and AMPK. β-lap may be a novel therapeutic agent for the treatment of lipotoxic cardiomyopathy.
authors.affiliation: College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Moon Hee
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Department of Life Science, Gachon University, Sungnam, Korea.
authors.forename: Nguyen Khoi Song
authors.initials: NK
authors.lastname: Tran
authors.affiliation: R&D Center, KT&G Life Sciences Corp., Suwon, Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.affiliation: Department of Oral Anatomy, School of Dentistry and Institute of Oral Biosciences, Chonbuk National University, Jeonju, Korea.
authors.forename: Byung Keon
authors.initials: BK
authors.lastname: Park
authors.affiliation: Department of Life Science, Gachon University, Sungnam, Korea.
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Life Science, Gachon University, Sungnam, Korea.
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.affiliation: Department of Oral Anatomy, School of Dentistry and Institute of Oral Biosciences, Chonbuk National University, Jeonju, Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Lee
authors.affiliation: College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.affiliation: College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Dong Kwon
authors.initials: DK
authors.lastname: Yang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism*; D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D008055:Lipids / Q000633:toxicity*; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009285:Naphthoquinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000214:Acyl Coenzyme A; D008055:Lipids; D009285:Naphthoquinones; D014280:Triglycerides; C014638:beta-lapachone; D000217:Acyltransferases; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1