| First Author | Zhang W | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 1280 |
| PubMed ID | 38342927 | Mgi Jnum | J:360437 |
| Mgi Id | MGI:7594904 | Doi | 10.1038/s41467-024-45520-8 |
| Citation | Zhang W, et al. (2024) Sonic hedgehog-heat shock protein 90beta axis promotes the development of nonalcoholic steatohepatitis in mice. Nat Commun 15(1):1280 |
| abstractText | Sonic hedgehog (SHH) and heat shock protein 90beta (HSP90beta) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90beta is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90beta ubiquitylation through deubiquitylase USP31, thus preventing HSP90beta degradation and promoting hepatic lipid synthesis. HSP90beta 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-kappaB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90beta 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-HSP90beta-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker. |
