title: Downregulation of adipose triglyceride lipase promotes cardiomyocyte hypertrophy by triggering the accumulation of ceramides.
abstract: Adipose triglyceride lipase (ATGL), the rate-limiting enzyme of triglyceride (TG) hydrolysis, plays an important role in TG metabolism. ATGL knockout mice suffer from TG accumulation and die from heart failure. However, the mechanisms underlying cardiac hypertrophy caused by ATGL dysfunction remain unknown. In this study, we found that ATGL expression declined in pressure overload-induced cardiac hypertrophy in vivo and phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. ATGL knockdown led to cardiomyocyte hypertrophy, while ATGL overexpression prevented PE-induced hypertrophy. In addition, ATGL downregulation increased but ATGL overexpression reduced the contents of ceramide, which has been proved to be closely associated with cardiac hypertrophy. Moreover, the accumulation of ceramide was due to elevation of free fatty acids in ATGL-knockdown cardiomyocytes, which could be explained by the reduced activity of peroxisome proliferator-activated receptor (PPAR) α leading to imbalance of fatty acid uptake and oxidation. These observations suggest that downregulation of ATGL causes the decreased PPARα activity which results in the imbalance of FA uptake and oxidation, elevating intracellular FFA contents to promote the accumulation of ceramides, and finally inducing cardiac hypertrophy. Upregulation of ATGL could be a strategy for ameliorating lipotoxic damage in cardiac hypertrophy.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China; Department of Pharmacology, School of Medicine, Jishou University, Jishou, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Xiao-jun
authors.initials: XJ
authors.lastname: Feng
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Zhuo-ming
authors.initials: ZM
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Si
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Yan-hong
authors.initials: YH
authors.lastname: He
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Jiao-jiao
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Pharmaceutical Department, The Second's People Hospital of Guangdong Province, Guangzhou, PR China.
authors.forename: Si-yu
authors.initials: SY
authors.lastname: Zeng
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Xue-ping
authors.initials: XP
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Xiao-yang
authors.initials: XY
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China. Electronic address: chshaor@mail.sysu.edu.cn.
authors.forename: Shao-rui
authors.initials: SR
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China. Electronic address: liupq@mail.sysu.edu.cn.
authors.forename: Pei-qing
authors.initials: PQ
authors.lastname: Liu
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002518:Ceramides / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D008049:Lipase / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000217:Acyltransferases
chemical_list: D002518:Ceramides; D008049:Lipase; D047493:PPAR alpha; C571275:PNPLA2 protein, rat; D000217:Acyltransferases
keywords: Adipose triglyceride lipase; Cardiac hypertrophy; Ceramide; Fatty acid oxidation; Fatty acid uptake