Sonic hedgehog-heat shock protein 90ß axis promotes the development of nonalcoholic steatohepatitis (RNA-Seq)

The incidence rate of nonalcoholic steatohepatitis (NASH) is on the rise with no effective clinical treatment available to date. Understanding the key molecular mechanism underlying the process of NASH can provide theoretical support for the development of safe and effective therapeutic drugs. Sonic hedgehog (SHH) and heat shock protein 90ß (HSP90ß) have been implicated in NASH but their molecular mechanisms of action remain elusive. HSP90ß was found to be a key SHH downstream molecule that promoted NASH processes In hepatocytes, SHH reduced HSP90ß ubiquitylation through deubiquitylase USP31, thus preventing HSP90ß degradation and promoting hepatic lipid synthesis. As an important component protein in the formation of exosomes, HSP90ß is high in high fructose, high fat, and high cholesterol (HFFC) diet-induced NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targets and decreases Rap1b levels, which in turn promote NF-?B transcriptional activity in macrophages and stimulate the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90ß axis, or delivery of miR-28-5p to macrophages in the liver, impaired NASH symptomatic development. Importantly, analysis of NASH patient sera revealed a markedly higher abundance of miR-28-5p compared to healthy donors. Taken together, the SHH-HSP90ß-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a novel NASH diagnostic biomarker. Overall design: Gene expression analysis using data from RNA-seq for exosomes in NASH or normal mice livers