SL010110, a lead compound, inhibits gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and improves glucose homeostasis in diabetic mice
文献类型：期刊论文
| 作者 | Ren, Yu-ran1,2; Ye, Yang-liang2 ; Feng, Ying2; Xu, Ti-fei2; Shen, Yu2; Liu, Jia3; Huang, Su-ling2; Shen, Jian-hua2; Leng, Ying1,2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2021-02-11 |
| 页码 | 13 |
| 关键词 | SL010110 gluconeogenesis primary mouse hepatocytes PEPCK1 acetylation degradation |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-020-00609-w |
| 通讯作者 | Huang, Su-ling(slhuang@simm.ac.cn) ; Shen, Jian-hua(jhshen@simm.ac.cn) ; Leng, Ying(yleng@simm.ac.cn) |
| 英文摘要 | Suppression of excessive hepatic gluconeogenesis is an effective strategy for controlling hyperglycemia in type 2 diabetes (T2D). In the present study, we screened our compounds library to discover the active molecules inhibiting gluconeogenesis in primary mouse hepatocytes. We found that SL010110 (5-((4-allyl-2-methoxyphenoxy) methyl) furan-2-carboxylic acid) potently inhibited gluconeogenesis with 3 mu M and 10 mu M leading to a reduction of 45.5% and 67.5%, respectively. Moreover, SL010110 caused suppression of gluconeogenesis resulted from downregulating the protein level of phosphoenolpyruvate carboxykinase 1 (PEPCK1), but not from affecting the gene expressions of PEPCK, glucose-6-phosphatase, and fructose-1,6-bisphosphatase. Furthermore, SL010110 increased PEPCK1 acetylation, and promoted PEPCK1 ubiquitination and degradation. SL010110 activated p300 acetyltransferase activity in primary mouse hepatocytes. The enhanced PEPCK1 acetylation and suppressed gluconeogenesis caused by SL010110 were blocked by C646, a histone acetyltransferase p300 inhibitor, suggested that SL010110 inhibited gluconeogenesis by activating p300. SL010110 decreased NAD(+)/NADH ratio, inhibited SIRT2 activity, and further promoted p300 acetyltransferase activation and PEPCK1 acetylation. These effects were blocked by NMN, an NAD(+) precursor, suggested that SL010110 inhibited gluconeogenesis by inhibiting SIRT2, activating p300, and subsequently promoting PEPCK1 acetylation. In type 2 diabetic ob/ob mice, single oral dose of SL010110 (100 mg/kg) suppressed gluconeogenesis accompanied by the suppressed hepatic SIRT2 activity, increased p300 activity, enhanced PEPCK1 acetylation and degradation. Chronic oral administration of SL010110 (15 or 50 mg/kg) significantly reduced the blood glucose levels in ob/ob and db/db mice. This study reveals that SL010110 is a lead compound with a distinct mechanism of suppressing gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and potent anti-hyperglycemic activity for the treatment of T2D. |
| 资助项目 | Science and Technology Commission of Shanghai Municipality[19431900900] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000617080700001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/295769]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Huang, Su-ling; Shen, Jian-hua; Leng, Ying |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ren, Yu-ran,Ye, Yang-liang,Feng, Ying,et al. SL010110, a lead compound, inhibits gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and improves glucose homeostasis in diabetic mice[J]. ACTA PHARMACOLOGICA SINICA,2021:13. |
| APA | Ren, Yu-ran.,Ye, Yang-liang.,Feng, Ying.,Xu, Ti-fei.,Shen, Yu.,...&Leng, Ying.(2021).SL010110, a lead compound, inhibits gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and improves glucose homeostasis in diabetic mice.ACTA PHARMACOLOGICA SINICA,13. |
| MLA | Ren, Yu-ran,et al."SL010110, a lead compound, inhibits gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and improves glucose homeostasis in diabetic mice".ACTA PHARMACOLOGICA SINICA (2021):13. |
入库方式： OAI收割
来源：上海药物研究所
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