| First Author | Mihara T | Year | 2024 |
| Journal | Hepatol Commun | Volume | 8 |
| Issue | 6 | PubMed ID | 38836815 |
| Mgi Jnum | J:360593 | Mgi Id | MGI:7834563 |
| Doi | 10.1097/HC9.0000000000000457 | Citation | Mihara T, et al. (2024) Nicotine aggravates liver fibrosis via alpha7 nicotinic acetylcholine receptor expressed on activated hepatic stellate cells in mice. Hepatol Commun 8(6) |
| abstractText | BACKGROUND: Smoking is a risk factor for liver cirrhosis; however, the underlying mechanisms remain largely unexplored. The alpha7 nicotinic acetylcholine receptor (alpha7nAChR) has recently been detected in nonimmune cells possessing immunoregulatory functions. We aimed to verify whether nicotine promotes liver fibrosis via alpha7nAChR. METHODS: We used osmotic pumps to administer nicotine and carbon tetrachloride to induce liver fibrosis in wild-type and alpha7nAChR-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 alpha7nAChR antagonist, methyllycaconitine citrate. RESULTS: Nicotine exacerbated carbon tetrachloride-induced liver fibrosis in mice (+42.4% in hydroxyproline assay). This effect of nicotine was abolished in alpha7nAChR-deficient mice, indicating nicotine promotes liver fibrosis via alpha7nAChR. To confirm the direct involvement of alpha7nAChRs in liver fibrosis, we investigated the effects of genetic suppression of alpha7nAChR expression on carbon tetrachloride-induced liver fibrosis without nicotine treatment. Profibrotic gene expression at 1.5 weeks was significantly suppressed in alpha7nAChR-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 alpha7nAChR 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 alpha7nAChR. CONCLUSIONS: Nicotine aggravates liver fibrosis induced by other factors by activating alpha7nAChR on HSCs, thereby increasing their collagen-producing capacity. We suggest the profibrotic effect of nicotine is mediated through alpha7nAChRs. |
