Mitochondrial Uncoupling Coordinated With PDH Activation Safely Ameliorates Hyperglycemia via Promoting Glucose Oxidation
文献类型：期刊论文
| 作者 | Jiang, Haowen1,3; Jin, Jia1,2; Duan, Yanan1; Xie, Zhifu3; Li, Yufeng3; Gao, Anhui3; Gu, Min3 ; Zhang, Xinwen3; Peng, Chang3; Xia, Chunmei3
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| 刊名 | DIABETES
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| 出版日期 | 2019-12-01 |
| 卷号 | 68期号:12页码:2197-2209 |
| ISSN号 | 0012-1797 |
| DOI | 10.2337/db19-0589 |
| 通讯作者 | Yang, Fan(fyang@chem.ecnu.edu.cn) ; Li, Jingya(jyli@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) |
| 英文摘要 | Uncoupling of mitochondrial respiration by chemical uncouplers has proven effective in ameliorating obesity, insulin resistance, and hyperglycemia. However, development of uncoupler-based therapy remains challenging due to its potentially lethal adverse effects. Here, we identify pyruvate dehydrogenase (PDH) as a key modifier of the toxicity profile of 2, 4-dinitrophenol (DNP), a prototypical mitochondrial uncoupler. PDH activation by dichloroacetic acid (DCA) protects mice from DNP-induced hyperlactacidemia, hyperthermia, and death while preserving the ability of DNP to promote fuel oxidation and improve insulin sensitivity in mice. Mechanistically, PDH activation switches on mitochondrial glucose oxidation to accommodate increased glycolytic flux, leading to reduced lactate secretion during uncoupler treatments. We devised a chemical screening strategy and discovered compound 6j as a dual-action compound that simultaneously activates PDH and uncouples mitochondrial respiration. Compound 6j exhibits an excellent efficacy and safety profile in restoring glucose homeostasis in diabetic mice. This work establishes a new principle to safely harness the power of chemical uncouplers for the treatment of metabolic disease. |
| WOS关键词 | INSULIN-RESISTANCE ; PYRUVATE-DEHYDROGENASE ; ADIPOSE-TISSUE ; OBESITY ; DINITROPHENOL ; AMILORIDE ; MICE ; HYPERTRIGLYCERIDEMIA ; 2,4-DINITROPHENOL ; INHIBITION |
| 资助项目 | National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[81673493] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDA12040301] ; Shanghai Science and Technology Commission[16JC1405000] ; K.C. Wong Education Foundation |
| WOS研究方向 | Endocrinology & Metabolism |
| 语种 | 英语 |
| 出版者 | AMER DIABETES ASSOC |
| WOS记录号 | WOS:000511994900002 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/281623]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yang, Fan; Li, Jingya; Li, Jia |
| 作者单位 | 1.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai, Peoples R China 2.Zhejiang Sci Tech Univ, Sch Life Sci, Hangzhou, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Jiang, Haowen,Jin, Jia,Duan, Yanan,et al. Mitochondrial Uncoupling Coordinated With PDH Activation Safely Ameliorates Hyperglycemia via Promoting Glucose Oxidation[J]. DIABETES,2019,68(12):2197-2209. |
| APA | Jiang, Haowen.,Jin, Jia.,Duan, Yanan.,Xie, Zhifu.,Li, Yufeng.,...&Li, Jia.(2019).Mitochondrial Uncoupling Coordinated With PDH Activation Safely Ameliorates Hyperglycemia via Promoting Glucose Oxidation.DIABETES,68(12),2197-2209. |
| MLA | Jiang, Haowen,et al."Mitochondrial Uncoupling Coordinated With PDH Activation Safely Ameliorates Hyperglycemia via Promoting Glucose Oxidation".DIABETES 68.12(2019):2197-2209. |
入库方式： OAI收割
来源：上海药物研究所
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