Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Hepatol Commun. 2024 Jun 5;8(6). doi: 10.1097/HC9.0000000000000457. eCollection 2024 Jun 1.
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.
吸烟是肝硬化的一个风险因素；然而，其潜在机制在很大程度上仍未得到探索。α7 烟碱型乙酰胆碱受体（α7nAChR）最近在具有免疫调节功能的非免疫细胞中被检测到。我们旨在验证尼古丁是否通过 α7nAChR 促进肝纤维化。
我们使用渗透泵给野生型和 α7nAChR 缺陷型小鼠给予尼古丁和四氯化碳以诱导肝纤维化。通过 Masson 三色染色、羟脯氨酸测定和实时 PCR 评估纤维化的严重程度，用于检测纤维化基因。此外，我们评估了尼古丁和 α7nAChR 拮抗剂甲基烟碱柠檬酸处理的人 HSCs 系 LX-2 和原代大鼠 HSCs 的细胞增殖能力和 COL1A1mRNA 表达。
尼古丁加剧了四氯化碳诱导的小鼠肝纤维化（羟脯氨酸测定增加 42.4%）。在 α7nAChR 缺陷型小鼠中，尼古丁的这种作用被消除，表明尼古丁通过 α7nAChR 促进肝纤维化。为了证实 α7nAChR 直接参与肝纤维化，我们在没有尼古丁处理的情况下，研究了基因抑制 α7nAChR 表达对四氯化碳诱导的肝纤维化的影响。在 1.5 周时，α7nAChR 缺陷型小鼠的纤维化基因表达显著受到抑制（Acta2 减少 83.8%，Col1a1 减少 80.6%，Tgfb1 减少 66.8%），而在 4 周时胶原含量减少（羟脯氨酸测定减少 22.3%）。体外分析显示，α7nAChR 在激活的但不是静止的 HSCs 中表达。用尼古丁处理 LX-2 细胞增加了 COL1A1 的表达（增加 116%）和细胞增殖（增加 10.9%）。这些作用被甲基烟碱柠檬酸减弱，表明尼古丁通过 α7nAChR 发挥致纤维化作用。
尼古丁通过激活 HSCs 上的 α7nAChR 加重其他因素诱导的肝纤维化，从而增加其产生胶原的能力。我们认为尼古丁的致纤维化作用是通过 α7nAChR 介导的。
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