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

Sonic hedgehog (SHH) and heat shock protein 90 beta (HSP90 beta) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90 beta is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90 beta ubiquitylation through deubiquitylase USP31, thus preventing HSP90 beta degradation and promoting hepatic lipid synthesis. HSP90 beta 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-kappa B transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90 beta 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-HSP90 beta-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker. The mechanistic involvement of sonic hedgehog signaling in nonalcoholic steatohepatitis is not clear. Here, the authors show that sonic hedgehog protein regulates the stability of HSP90 beta, enabling hepatocytes to secrete exosomes containing miR-28-5-p to promote NASH development.