Increased Dynamin-Related Protein 1-Dependent Mitochondrial Fission Contributes to High-Fat-Diet-Induced Cardiac Dysfunction and Insulin Resistance by Elevating Tafazzin in Mouse Hearts
Increased Dynamin-Related Protein 1-Dependent Mitochondrial Fission Contributes to High-Fat-Diet-Induced Cardiac Dysfunction and Insulin Resistance by Elevating Tafazzin in Mouse Hearts
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DOI：
10.1002/mnfr.201801322
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发表时间：
2019-04-01
影响因子：
5.2
通讯作者：
Wang, Jianxun
中科院分区：
文献类型：
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作者：
Chang, Wenguang;Xiao, Dandan;Wang, Jianxun
高脂肪（HF）饮食引起的胰岛素抵抗是心血管疾病发病的主要因素。然而，调节心脏胰岛素信号的分子机制尚不完全清楚。研究了他法嗪对高氟饮食小鼠心脏的调节作用。方法和结果小鼠分别饲喂HF饲粮和低脂饲粮24周。24周后，研究人员发现hf饮食引起的心功能障碍与线粒体蛋白tafazzin的过度表达有关。他法津增加可促进线粒体分裂并损害胰岛素信号，这是由动力蛋白相关蛋白1 （Drp-1）从细胞质转运到线粒体介导的。此外，用siRNA敲低他法津可抑制棕榈酸诱导的线粒体裂变并恢复胰岛素敏感性。此外，miR-125b-5p作为针对他法嗪的上游调节因子被确定，棕榈酸盐诱导的胰岛素抵抗进一步得到拯救。结论在高氟饮食喂养的小鼠心脏中，他法津增加通过介导Drp-1转位至线粒体参与胰岛素抵抗，而一种小的非编码RNA miR-125b-5p至少部分调控了这一信号通路并减轻了胰岛素抵抗。
Scope High fat (HF)-diet-induced insulin resistance is a major contributor to the pathogenesis of cardiovascular diseases. However, the molecular mechanisms that regulate cardiac insulin signaling are not fully understood. The regulatory role of tafazzin in the hearts of HF-diet-fed mice is investigated. Methods and results Mice are fed a HF diet or low fat (LF) diet for up to 24 weeks. After 24 weeks, it is found that HF-diet-induced cardiac dysfunction is linked to overexpression of the mitochondrial protein tafazzin. Increased tafazzin promotes mitochondrial fission and impairs insulin signaling, which is mediated by dynamin-related protein 1 (Drp-1) translocation from the cytosol to the mitochondria. Furthermore, knockdown of tafazzin with siRNA inhibits palmitic-acid-induced mitochondrial fission and restores insulin sensitivity. Moreover, miR-125b-5p as an upstream regulator targeting tafazzin is identified and palmitate-induced insulin resistance further rescued. Conclusion In HF-diet-fed mouse hearts, increased tafazzin contributes to insulin resistance via mediating Drp-1 translocation to the mitochondria, and a small non-coding RNA, miR-125b-5p, at least partially regulates this signaling pathway and alleviates insulin resistance.