Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada; Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA.
Cell Metab. 2018 Feb 6;27(2):450-460.e6. doi: 10.1016/j.cmet.2017.11.003. Epub 2017 Dec 21.
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.
肠促胰岛素激素除了在胰腺之外还发挥着多种代谢作用。尽管心脏表达两种肠促胰岛素受体，但 GIP 受体（GIPR）作用的心脏生物学仍不完全清楚。在这里，我们表明 GIPR 激动剂不会损害心脏对缺血的反应。相比之下，Gipr 的基因缺失减少了心肌梗死（MI）诱导的心室损伤，并提高了存活率，同时降低了激素敏感脂肪酶（HSL）的磷酸化；它还增加了心肌三酰基甘油（TAG）的储存。相反，在分离的心脏中直接 GIPR 激动剂减少了心肌 TAG 的储存并增加了脂肪酸氧化。在 Gipr 小鼠中，HSL 的药理学激活或基因过表达部分逆转了这种心脏保护表型。心肌细胞中选择性 Gipr 失活模拟了 Gipr 小鼠，导致实验性 MI 后存活率提高和不良重塑减少。因此，心肌细胞 GIPR 调节脂肪酸代谢和对缺血性心脏损伤的适应性反应。这些发现对于开发基于 GIPR 的治疗方法具有转化意义。
