ReferenceID 132
Inhibition of HSP90β Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System
Theranostics
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
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- Reference Id
- 132
- Evidence Id
- 16722
- Core Evidence Id
- 16722
- Source Reference Id
- 222
- Herb2 Reference Id
- HBREF000425
- Subject Paper Key
- HBIN021561_31534518
- Pubmed Id
- 31534518
- Doi
- 10.7150/thno.36505
- Paper Title
- Inhibition of HSP90β Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System
- Paper 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 HSP90β. 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 HSP90β, rather than HSP90α, was overexpressed in NAFLD patients and obese mice. Hepatic HSP90β was also clinical relevant to serum lipid level. Depletion of HSP90β promoted mature sterol regulatory element-binding proteins (mSREBPs) degradation through Akt-GSK3β-FBW7 pathway, thereby dramatically decreased the content of neutral lipids and cholesterol. We discovered an HSP90β-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: HSP90β plays a parolog-specific role in regulating lipid homeostasis. Compound that selectively inhibits HSP90β could be useful in the clinic for the treatment for metabolic diseases.
- Journal
- Theranostics
- Publish Year
- 2019
- Experiment Subject
- hek293t cell lines,hl-7702 cells,hh (human hepatocytes) cells, diet induced obese (dio) mice
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Metabolic Diseases
- Paper Title Cn
- Paper Title En
- Inhibition of HSP90β Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System
- Bilingual Status
- semi_complete