Nicotine aggravates liver fibrosis via α7 nicotinic acetylcholine receptor expressed on activated hepatic stellate cells in mice

• Published in: Hepatology communications Vol. 8; no. 6
• Main Authors: Mihara, Taiki, Hori, Masatoshi
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 01.06.2024
• Subjects: Aconitine - analogs & derivatives; Aconitine - pharmacology; alpha7 Nicotinic Acetylcholine Receptor - genetics; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Carbon Tetrachloride; Cell Line; Cell Proliferation - drug effects; Collagen Type I - metabolism; Collagen Type I, alpha 1 Chain - metabolism; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Humans; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotine - adverse effects; Nicotinic Agonists - pharmacology; Original; Rats; Transforming Growth Factor beta1 - metabolism
• ISSN: 2471-254X; 2471-254X
• DOI: 10.1097/HC9.0000000000000457

Smoking is a risk factor for liver cirrhosis; however, the underlying mechanisms remain largely unexplored. The α7 nicotinic acetylcholine receptor (α7nAChR) has recently been detected in nonimmune cells possessing immunoregulatory functions. We aimed to verify whether nicotine promotes liver fibrosis via α7nAChR. We used osmotic pumps to administer nicotine and carbon tetrachloride to induce liver fibrosis in wild-type and α7nAChR-deficient mice. The severity of fibrosis was evaluated using Masson trichrome staining, hydroxyproline assays, and real-time PCR for profibrotic genes. Furthermore, we evaluated the cell proliferative capacity and COL1A1 mRNA expression in human HSCs line LX-2 and primary rat HSCs treated with nicotine and an α7nAChR antagonist, methyllycaconitine citrate. Nicotine exacerbated carbon tetrachloride-induced liver fibrosis in mice (+42.4% in hydroxyproline assay). This effect of nicotine was abolished in α7nAChR-deficient mice, indicating nicotine promotes liver fibrosis via α7nAChR. To confirm the direct involvement of α7nAChRs in liver fibrosis, we investigated the effects of genetic suppression of α7nAChR expression on carbon tetrachloride-induced liver fibrosis without nicotine treatment. Profibrotic gene expression at 1.5 weeks was significantly suppressed in α7nAChR-deficient mice (-83.8% in Acta2, -80.6% in Col1a1, -66.8% in Tgfb1), and collagen content was decreased at 4 weeks (-22.3% in hydroxyproline assay). The in vitro analysis showed α7nAChR expression in activated but not in quiescent HSCs. Treatment of LX-2 cells with nicotine increased COL1A1 expression (+116%) and cell proliferation (+10.9%). These effects were attenuated by methyllycaconitine citrate, indicating the profibrotic effects of nicotine via α7nAChR. Nicotine aggravates liver fibrosis induced by other factors by activating α7nAChR on HSCs, thereby increasing their collagen-producing capacity. We suggest the profibrotic effect of nicotine is mediated through α7nAChRs.