期刊
CELL METABOLISM
卷 27, 期 2, 页码 450-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2017.11.003
关键词
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资金
- Canadian Institutes of Health Research (CIHR)
- Alberta Innovates-Health Solutions
- Banting and Best Diabetes Centre (BBDC)
- CIHR [82700, 154321]
- BBDC
- Canadian Diabetes Association (CDA)
- CDA
- Heart and Stroke Foundation of Ontario [G-14-0005953]
- Merck
- Novo Nordisk
- Canada Research Chair in Regulatory Peptides
- Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology
- MSD
- Takeda Pharmaceuticals
- Sanofi
- Taisho Toyama Pharmaceuticals
- Eli Lilly and Company
- Mitsubishi Tanabe Pharma
- Ono Pharmaceutical
- Kowa
- Astellas Pharma
- Boehringer Ingelheim
Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr(-/-) mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr(-/-) mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics.
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