title: Protective effects of Acyl-coA thioesterase 1 on diabetic heart via PPARα/PGC1α signaling.
abstract: BACKGROUND
  Using fatty acids (FAs) exclusively for ATP generation was reported to contribute to the development of diabetic cardiomyopathy. We studied the role of substrate metabolism related genes in the heart of the diabetes to find out a novel therapeutic target for diabetic cardiomyopathy.
  
  
  RESULTS
  By microarray analysis of metabolic gene expression, acyl-CoA thioesterase 1 (acot1) was clearly upregulated in the myocardia of db/db mice, compared with normal control C57BL/Ks. Therefore, gain-of-function and loss-of-function approaches were employed in db/db mice to investigate the functions of ACOT1 in oxidative stress, mitochondrial dysfunction and heart function. We found that in the hearts of db/db mice which overexpressed ACOT1, H(2)O(2) and malondialdehyde (MDA) were reduced, the activities of ATPases in mitochondria associated with mitochondrial function were promoted, the expression of uncoupling protein 3 (UCP3) contributing to oxygen wastage for noncontractile purposes was decreased, and cardiac dysfunction was attenuated, as determined by both hemodynamic and echocardiographic detections. Consistently, ACOT1 deficiency had opposite effects, which accelerated the cardiac damage induced by diabetes. Notably, by real-time PCR, we found that overexpression of ACOT1 in diabetic heart repressed the peroxisome proliferator-activated receptor alpha/PPARγ coactivator 1α (PPARα/PGC1α) signaling, as shown by decreased expression of PGC1α and the downstream genes involved in FAs use.
  
  
  CONCLUSIONS
  Our results demonstrated that ACOT1 played a crucial protective role in diabetic heart via PPARα/PGC1α signaling.
authors.affiliation: Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, P. R. China.
authors.forename: Shenglan
authors.initials: S
authors.lastname: Yang
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Rao
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Quanlu
authors.initials: Q
authors.lastname: Duan
authors.forename: Fuqiong
authors.initials: F
authors.lastname: Chen
authors.forename: Guangwen
authors.initials: G
authors.lastname: Long
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D058065:Diabetic Cardiomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013869:Thiolester Hydrolases / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D013869:Thiolester Hydrolases; C447830:Acot1 protein, mouse; D000251:Adenosine Triphosphatases