Inhibition of HSP90 beta Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System

doi:10.7150/thno.36505

	Inhibition of HSP90 beta Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System
	Zheng, Zu-Guo 1; Zhang, Xin 1; Liu, Xiao-Xiao 1; Jin, Xiu-Xiu 4,5,6; Dai, Lunzhi 4,5,6; Cheng, Hui-Min 1; Jing, Dan 1; Pyone Myat Thu 1; Zhang, Mu 1; Li, Hongyang 7
刊名	THERANOSTICS
	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
通讯作者	Liu, Junli(liujunli@sjtu.edu.cn) ; Li, Hui-Jun(cpuli@163.com) ; Li, Ping(liping2004@126.com) ; Xu, Xiaojun(xiaojunxu@cpu.edu.cn)
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.
资助项目	National Science Foundation of China[81773957] ; National Science Foundation of China[81421005] ; National Science Foundation of China[81322051] ; National Science Foundation of China[31722028] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2019ZX09201001-001-001] ; 111 Project[B16046] ; State Key Laboratory of Natural Medicines, China Pharmaceutical University[SKLNMZZCX201820] ; State Key Laboratory of Natural Medicines[SKLNMKF201706] ; Double First-Class University Project[CPU2018GF04] ; China Postdoctoral Science Foundation[2018M642380]
WOS关键词	DE-NOVO LIPOGENESIS ; ALCOHOLIC LIVER-DISEASE ; TRANSCRIPTION FACTORS ; MIDDLE DOMAIN ; PPAR-GAMMA ; PROTEIN ; BINDING ; CHOLESTEROL ; METABOLISM ; HEAT-SHOCK-PROTEIN-90
WOS研究方向	Research & Experimental Medicine
语种	英语
出版者	IVYSPRING INT PUBL
WOS记录号	WOS:000481601200004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288931]
专题	中国科学院上海药物研究所
通讯作者	Liu, Junli; Li, Hui-Jun; Li, Ping; Xu, Xiaojun
作者单位	1.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China 2.China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Jiangsu, Peoples R China 3.Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Endocrinol & Metab, Shanghai Diabet Inst, Shanghai 200233, Peoples R China 4.Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Dept Gen Practice, Chengdu 610041, Sichuan, Peoples R China 5.Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Lab PTM, Chengdu 610041, Sichuan, Peoples R China 6.Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China 7.Peking Union Med Coll, Chinese Acad Med Sci, Inst Dermatol, Nanjing 210009, Jiangsu, Peoples R China 8.Hangzhou First Peoples Hosp, Dept Infect Dis, Hangzhou 310006, Zhejiang, Peoples R China 9.Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing 210093, Jiangsu, Peoples R China 10.Nanjing Univ, Jiangsu Key Lab Mol Med, Nanjing 210093, Jiangsu, 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.,Jin, Xiu-Xiu.,Dai, Lunzhi.,...&Xu, Xiaojun.(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.