Sodium Butyrate Protects -Against High Fat Diet-Induced Cardiac Dysfunction and Metabolic Disorders in Type II Diabetic Mice.
Sodium Butyrate Protects -Against High Fat Diet-Induced Cardiac Dysfunction and Metabolic Disorders in Type II Diabetic Mice.
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DOI：
10.1002/jcb.25902
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发表时间：
2017-08
影响因子：
4
通讯作者：
Zhao TC
中科院分区：
文献类型：
--
作者：
Zhang L;Du J;Yano N;Wang H;Zhao YT;Dubielecka PM;Zhuang S;Chin YE;Qin G;Zhao TC
组蛋白脱乙酰酶是心脏病理生理学和代谢紊乱的关键调节因子。然而，组蛋白脱乙酰酶(HDAC)在控制II型糖尿病和肥胖症患者心功能中的作用仍不清楚。在这里，我们确定HDAC抑制是否可以减轻高脂饮食(HFD)引起的心功能障碍并改善代谢特征。成年小鼠喂饲高脂饲料或标准饲料24周。从12周开始，将小鼠随机分成四组，分别给饲喂饲料和高脂饲料的小鼠饮水中添加1%的丁酸钠。评估糖耐量、代谢参数、心功能和重塑。安乐死后24周取材进行组织学分析和细胞信号转导。高脂饲料喂养的小鼠表现出心肌功能障碍和严重的间质纤维化，这些都可以通过HDAC抑制来减轻。HFD诱导的代谢综合征以胰岛素抵抗、肥胖、高胰岛素血症、高血糖、脂质堆积和心肌肥厚为特征，这些影响可通过HDAC抑制来预防。此外，HDAC抑制减少了心肌细胞的凋亡，减少了活性氧的产生，并增加了HFD喂养的心肌中的血管生成。值得注意的是，HFD诱导MKK3、p38、p38调节/激活蛋白激酶(PRAK)和Akt-1的表达减少，但不影响p44/42的磷酸化，这一作用可被HDAC抑制所阻止。这些结果提示，HDAC抑制在肥胖和糖尿病患者维持心功能和减轻代谢紊乱方面起着关键作用，这与MKK3/p38/PRAK通路有关。这项研究有望开发一种新的治疗策略，用于治疗II型糖尿病引起的心力衰竭和代谢紊乱。
Histone deacetylases are recently identified to act as key regulators for cardiac pathophysiology and metabolic disorders. However, the function of histone deacetylase (HDAC) in controlling cardiac performance in type II diabetes and obesity remains unknown. Here we determine whether HDAC inhibition attenuates high fat diet (HFD)-induced cardiac dysfunction and improves metabolic features. Adult mice were fed with either HFD or standard chow food for 24 weeks. Starting at 12 weeks, mice were divided into four groups randomly, in which sodium butyrate (1%), a potent HDAC inhibitor, was provided to chow and HFD-fed mice in drinking water, respectively. Glucose intolerance, metabolic parameters, cardiac function, and remodeling were assessed. Histological analysis and cellular signaling were examined at 24 weeks following euthanization of mice. HFD-fed mice demonstrated myocardial dysfunction and profound interstitial fibrosis, which were attenuated by HDAC inhibition. HFD-induced metabolic syndrome features insulin resistance, obesity, hyperinsulinemia, hyperglycemia, lipid accumulations, and cardiac hypertrophy, these effects were prevented by HDAC inhibition. Furthermore, HDAC inhibition attenuated myocyte apoptosis, reduced production of reactive oxygen species, and increased angiogenesis in the HFD-fed myocardium. Notably, HFD induced decreases in MKK3, p38, p38 regulated/activated protein kinase (PRAK) and Akt-1, but not p44/42 phosphorylation, which were prevented by HDAC inhibition. These results suggest that HDAC inhibition plays a critical role to preserve cardiac performance and mitigate metabolic disorders in obesity and diabetes, which is associated with MKK3/p38/PRAK pathway. The study holds promise in developing a new therapeutic strategy in the treatment of type II diabetic-induced heart failure and metabolic disorders.