Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice

Weitao Zhang, Junfeng Lu, Lianshun Feng, Hanyue Xue, Shiyang Shen, Shuiqing Lai, PingPing Li, Ping Li, Jian Kuang, Zhiwei Yang () and Xiaojun Xu ()
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Weitao Zhang: Zhejiang University
Junfeng Lu: Capital Medical University
Lianshun Feng: China Pharmaceutical University
Hanyue Xue: China Pharmaceutical University
Shiyang Shen: China Pharmaceutical University
Shuiqing Lai: Guangdong Academy of Medical Sciences
PingPing Li: Diabetes Research Center of Chinese Academy of Medical Sciences
Ping Li: China Pharmaceutical University
Jian Kuang: Guangdong Academy of Medical Sciences
Zhiwei Yang: Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical Collage (PUMC)
Xiaojun Xu: Zhejiang University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Sonic hedgehog (SHH) and heat shock protein 90β (HSP90β) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90β is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90β ubiquitylation through deubiquitylase USP31, thus preventing HSP90β degradation and promoting hepatic lipid synthesis. HSP90β significantly increases in NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes NF-κB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90β axis, or delivery of miR-28-5p to macrophages in the male mice liver, impairs NASH symptomatic development. Importantly, there is a markedly higher abundance of miR-28-5p in NASH patient sera. Taken together, the SHH-HSP90β-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker.

Date: 2024
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DOI: 10.1038/s41467-024-45520-8

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