Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans
Open accessAbstract
Metabolic 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.
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RNA-seq and qPCR identified a decrease in characteristic hepatocyte-enriched genes with roles in metabolism, regeneration and MASLD/ALD, such as Cyp1a2, Cyp2e1, Ang, Gulo, Hsd3b5, Avpr1a and Chrna4, and an increase in Cyp2f2 in HSC-depleted livers.
“Using RNA sequencing (RNA-seq) and quantitative PCR (qPCR), we identified a decrease in characteristic hepatocyte-enriched genes with roles in metabolism, regeneration and the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD), such as cytochrome P450 oxidases Cyp1a2 and Cyp2e1, and Ang, Gulo, Hsd3b5, Avpr1a and Chrna426–28 as we”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [28]
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- Authors
- Pan, C., Liu, J., Gao, Y., Yang, M., Hu, H., Liu, C., Qian, M., Yuan, H.-Y., Yang, S., Zheng, M.-H., & Wang, L.
- Affiliations
- China Pharmaceutical University (CN)
- Nanjing University (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Capital Medical University (CN)
- Corresponding author
- Yang, Song
- Zheng, Ming-Hua
- Wang, Lirui
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2023-12
- Volume
- 35
- Issue
- 12
- Pages
- 2231-2249.e7
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W4389331981
- Cited by
- 27
- References
- 0
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 2
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- China Pharmaceutical University
- Nanjing University of Information Science and Technology
- University of California, San Diego
- Nanjing University
- National Key Research and Development Program of China (2018YFC1704900, 2018YFC1704905)
- Texas A&M University Health Science Center
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- CHRNA4, nicotinic acetylcholine receptors, nonalcoholic steatohepatitis, acetylcholine, smoking, nicotine, hepatocytes, immune cells, calcium influx, inflammatory signaling, cytokines, liver inflammation, therapeutic target
- MeSH terms
- Acetylcholine, Animals, Fatty Liver, Humans, Smoking, Polymorphism, Single Nucleotide, Hepatocytes, Mice
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