Inhibition of HSP90? Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System.
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ABSTRACT: 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?. 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?, rather than HSP90?, was overexpressed in NAFLD patients and obese mice. Hepatic HSP90? was also clinical relevant to serum lipid level. Depletion of HSP90? promoted mature sterol regulatory element-binding proteins (mSREBPs) degradation through Akt-GSK3?-FBW7 pathway, thereby dramatically decreased the content of neutral lipids and cholesterol. We discovered an HSP90?-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? plays a parolog-specific role in regulating lipid homeostasis. Compound that selectively inhibits HSP90? could be useful in the clinic for the treatment for metabolic diseases.
SUBMITTER: Zheng ZG
PROVIDER: S-EPMC6735373 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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