Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans

Cell Metab. 2023 Dec 5;35(12):2231-2249.e7. doi: 10.1016/j.cmet.2023.10.018.ABSTRACTMetabolic dysfunction-associated steatohepatitis (MASH) is a leading risk factor for liver cirrhosis and hepatocellular carcinoma. Here, we report that CHRNA4, a subunit of nicotinic acetylcholine receptors (nAChRs), is an accelerator of MASH progression. CHRNA4 also mediates the MASH-promotive effects induced by smoking. Chrna4 was expressed specifically in hepatocytes and exhibited increased levels in mice and patients with MASH. Elevated CHRNA4 levels were positively correlated with MASH severity. We further revealed that during MASH development, acetylcholine released from immune cells or nicotine derived from smoking functioned as an agonist to activate hepatocyte-intrinsic CHRNA4, inducing calcium influx and activation of inflammatory signaling. The communication between immune cells and hepatocytes via the acetylcholine-CHRNA4 axis led to the production of a variety of cytokines, eliciting inflammation in liver and promoting the pathogenesis of MASH. Genetic and pharmacological inhibition of CHRNA4 protected mice from diet-induced MASH. Targeting CHRNA4 might be a promising strategy for MASH therapeutics.PMID:38056431 | DOI:10.1016/j.cmet.2023.10.018

Source: Cell Metabolism - December 6, 2023 Category: Cytology Authors: Chuyue Pan Jun Liu Yingsheng Gao Maohui Yang Haiyang Hu Chang Liu Minyi Qian Hai-Yang Yuan Song Yang Ming-Hua Zheng Lirui Wang Source Type: research