Mus musculus Raw sequence reads
Nonalcoholic steatohepatitis (NASH) is a leading risk factor for liver cirrhosis and hepatocellular carcinoma, identifying the effective pharmacological therapy is thus indispensable and urgent. Here, we report that CHRNA4, a subunit of nicotine acetylcholine receptors (nAChRs), is an accelerator of NASH progression. CHRNA4 also mediates the pro-NASH effects induced by smoking exposure. In detail, Chrna4 was expressed specifically in hepatocytes and its expression was increased in mice and patients with NASH. Elevated CHRNA4 levels were positively correlated with the severity of NASH. We further revealed that, during the development of NASH, acetylcholine released from immune cells or nicotine derived from cigarette smoking functioned as an agonist, activated hepatocyte-intrinsic CHRNA4, induced calcium influx and the activation of inflammatory signaling pathways. The communication between immune cells and hepatocytes via the acetylcholine-CHRNA4 axis led to the production of a variety of cytokines, eliciting the inflammation in liver and promoting the pathogenesis of NASH. Genetic and pharmacological inhibition of CHRNA4 protected mice from diet-induced NASH progression. Targeting CHRNA4 might be a novel strategy for NASH therapeutics.