Gao Qian, Bi Pinduan, Mi Qili, Guan Ying, Jiang Jiarui, Li Xuemei, Yang Bin
Yunnan Key Laboratory of Tobacco Chemistry, R&D Center of China Tobacco Yunnan Industrial Co. Ltd., Kunming, Yunnan 650106, P.R. China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
Exp Ther Med. 2023 Jan 3;25(2):84. doi: 10.3892/etm.2023.11783. eCollection 2023 Feb.
Gallstones are diseases of the biliary system caused by cholesterol supersaturation and/or deficiency in bile salts in bile. Early studies have shown that symptomatic gallstones are primarily a disease of non-smokers, raising the possibility that nicotine can prevent gallstone formation. The present study investigated the effect of nicotine on the formation of cholesterol gallstone in C57BL/6J mice. C57BL/6J mice (eight-weeks-old) were fed a normal or lithogenic diet (basic feed 82.45%, fat 15.8%, cholesterol 1.25% and sodium cholate 0.5%) and divided into five groups: normal diet (ND); ND + high dose nicotine (H); lithogenic diet (LD); LD + low dose nicotine (L) and LD + nicotine (H). They were treated with or without nicotine injection for 10 weeks. Nicotine treatment did not change the rate of cholesterol gallstone formation. There was no difference in TNFα, IL-1β and IL-6 among the five groups. The LD group showed the highest cholesterol levels and there was significant suppression of the total cholesterol, low-density lipoprotein-cholesterol and total bile acid levels in the serum of the nicotine-treated mice. Quantitative PCR showed nicotine altered few bile acid metabolism-related genes expression in liver tissue and significantly altered cholesterol-metabolism genes in gallbladder tissue. Hematoxylin and eosin staining and western blotting showed that protein levels of farnesoid X receptor (FXR) and megalin in the gallbladder increased in the lithogenic-diet mice, which was significantly suppressed in the nicotine-treated mice. In vitro studies using gallbladder epithelial cells showed that chenodeoxycholic acids increased megalin expression, which could be attenuated by nicotine. Nicotine could regulate bile acid metabolism via the FXR-megalin/cubilin pathways, which potentially contribute to cholesterol nucleation and subsequent gallstone formation.
胆结石是由胆汁中胆固醇过饱和和/或胆汁盐缺乏引起的胆道系统疾病。早期研究表明，有症状的胆结石主要是非吸烟者的疾病，这增加了尼古丁可预防胆结石形成的可能性。本研究调查了尼古丁对C57BL/6J小鼠胆固醇结石形成的影响。将八周龄的C57BL/6J小鼠喂食正常或致石性饮食（基础饲料82.45%、脂肪15.8%、胆固醇1.25%和胆酸钠0.5%），并分为五组：正常饮食（ND）组；ND + 高剂量尼古丁（H）组；致石性饮食（LD）组；LD + 低剂量尼古丁（L）组和LD + 尼古丁（H）组。对它们进行有无尼古丁注射处理10周。尼古丁处理并未改变胆固醇结石的形成率。五组之间的TNFα、IL-1β和IL-6没有差异。LD组的胆固醇水平最高，尼古丁处理的小鼠血清中的总胆固醇、低密度脂蛋白胆固醇和总胆汁酸水平受到显著抑制。定量PCR显示尼古丁仅改变了肝脏组织中少数胆汁酸代谢相关基因的表达，并显著改变了胆囊组织中胆固醇代谢基因的表达。苏木精和伊红染色以及蛋白质印迹显示，致石性饮食小鼠胆囊中法尼醇X受体（FXR）和巨膜蛋白的蛋白质水平升高，而在尼古丁处理的小鼠中受到显著抑制。使用胆囊上皮细胞的体外研究表明，鹅去氧胆酸可增加巨膜蛋白的表达，而尼古丁可减弱这种作用。尼古丁可通过FXR-巨膜蛋白/立方体型蛋白途径调节胆汁酸代谢，这可能促进胆固醇成核及随后的胆结石形成。
