Inhibition of HSP90 beta Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System
文献类型：期刊论文
| 作者 | Zheng, Zu-Guo13; Zhang, Xin13; Liu, Xiao-Xiao13; Cheng, Hui-Min13; Jing, Dan13; Pyone Myat Thu13; Zhang, Mu13; Liu, Chang13; Li, Hui-Jun13; Li, Ping13 |
| 刊名 | THERANOSTICS
 |
| 出版日期 | 2019 |
| 卷号 | 9期号:20页码:5769-5783 |
| 关键词 | HSP90 beta lipid metabolism corylin SREBPs proteasomal degradation |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.36505 |
| 文献子类 | Article |
| 英文摘要 | Rationale: Heat shock protein 9 (HSP90) are a family of the most highly expressed cellular proteins and attractive drug targets against cancer, neurodegeneration diseases, etc. HSP90 proteins have also been suggested to be linked to lipid metabolism. However, the specific function of HSP90 paralogs, as well as the underlying molecular cascades remains largely unknown. This study aims to unravel the paralog-specific role of HSP90 in lipid metabolism and try to discover paralog-specific HSP90 inhibitors. Methods: In non-alcohol fatty liver disease (NAFLD) patients, as well as in diet induced obese (DIO) mice, expression of HSP90 paralogs were analyzed by immunohistochemistry and western blot. In hepatocytes and in DIO mice, HSP90 proteins were knockdown by siRNAs/shRNAs, metabolic parameters, as well as downstream signaling were then investigated. By virtue screening, corylin was found to bind specifically to HSP90 beta. Using photo-affinity labeling and mass spectrum, corylin binding proteins were identified. After oral administration of corylin, its lipid lowering effects in different metabolic disease mice models were evaluated. Results: We showed that hepatic HSP90 beta, rather than HSP90 alpha, was overexpressed in NAFLD patients and obese mice. Hepatic HSP90 beta was also clinical relevant to serum lipid level. Depletion of HSP90 beta promoted mature sterol regulatory element-binding proteins (mSREBPs) degradation through Akt-GSK3 beta-FBW7 pathway, thereby dramatically decreased the content of neutral lipids and cholesterol. We discovered an HSP90 beta-selective inhibitor (corylin) that only bound to its middle domain. We found that corylin treatment partially suppressed Akt activity only at Thr308 site and specifically promoted mSREBPs ubiquitination and proteasomal degradation. Corylin treatment significantly reduced lipid content in both liver cell lines and human primary hepatocytes. In animal studies, we showed that corylin ameliorated obesity-induced fatty liver disease, type 2 diabetes and atherosclerosis. Principle conclusions: HSP90 beta plays a parolog-specific role in regulating lipid homeostasis. Compound that selectively inhibits HSP90 beta could be useful in the clinic for the treatment for metabolic diseases. |
| 学科主题 | Research & Experimental Medicine |
| WOS关键词 | DE-NOVO LIPOGENESIS ; ALCOHOLIC LIVER-DISEASE ; TRANSCRIPTION FACTORS ; MIDDLE DOMAIN ; PPAR-GAMMA ; PROTEIN ; BINDING ; CHOLESTEROL ; METABOLISM ; HEAT-SHOCK-PROTEIN-90 |
| 语种 | 英语 |
| WOS记录号 | WOS:000481601200004 |
| 出版者 | IVYSPRING INT PUBL |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/610]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所 |
| 作者单位 | 1.Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Dept Gen Practice, Chengdu 610041, Sichuan, Peoples R China; 2.Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Lab PTM, Chengdu 610041, Sichuan, Peoples R China; 3.Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China; 4.Peking Union Med Coll, Chinese Acad Med Sci, Inst Dermatol, Nanjing 210009, Jiangsu, Peoples R China; 5.Hangzhou First Peoples Hosp, Dept Infect Dis, Hangzhou 310006, Zhejiang, Peoples R China; 6.Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing 210093, Jiangsu, Peoples R China; 7.Nanjing Univ, Jiangsu Key Lab Mol Med, Nanjing 210093, Jiangsu, Peoples R China; 8.Nanjing Univ, Sch Med, Nanjing 210093, Jiangsu, Peoples R China; 9.Chinese Acad Sci, Univ Chinese Acad Sci, Key Lab Nutr & Metab, Inst Nutr Sci,Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China; 10.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zheng, Zu-Guo,Zhang, Xin,Liu, Xiao-Xiao,et al. Inhibition of HSP90 beta Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System[J]. THERANOSTICS,2019,9(20):5769-5783. |
| APA | Zheng, Zu-Guo.,Zhang, Xin.,Liu, Xiao-Xiao.,Cheng, Hui-Min.,Jing, Dan.,...&,.(2019).Inhibition of HSP90 beta Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System.THERANOSTICS,9(20),5769-5783. |
| MLA | Zheng, Zu-Guo,et al."Inhibition of HSP90 beta Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System".THERANOSTICS 9.20(2019):5769-5783. |
入库方式： OAI收割
来源：上海营养与健康研究所
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