Effect of nicotine on cholesterol gallstone formation in C57BL/6J mice fed on a lithogenic diet

Gao,Qian; Bi,Pinduan; Mi,Qili; Guan,Ying; Jiang,Jiarui; Li,Xuemei; Yang,Bin

doi:10.3892/etm.2023.11783

Effect of nicotine on cholesterol gallstone formation in C57BL/6J mice fed on a lithogenic diet

Authors:
- Qian Gao
- Pinduan Bi
- Qili Mi
- Ying Guan
- Jiarui Jiang
- Xuemei Li
- Bin Yang
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Affiliations: 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
Published online on: January 3, 2023 https://doi.org/10.3892/etm.2023.11783
Article Number: 84
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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