Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan.
Department of Gastroenterology, Lishui Hospital, Zhejiang University School of Medicine, Lishui, Zhejiang, People's Republic of China.
Arch Toxicol. 2019 Jun;93(6):1713-1725. doi: 10.1007/s00204-019-02440-7. Epub 2019 Apr 19.
Previous epidemiological studies have suggested a link between high-cholesterol intake and liver disease progression, including hepatocellular carcinoma (HCC). However, the precise mechanism of hepatotoxicity and hepatocarcinogenesis caused by excessive cholesterol consumption remains unclear. We aimed to investigate the impact of dietary cholesterol using hepatitis C virus core gene transgenic (HCVcpTg) mice, which spontaneously developed HCC with age. Male HCVcpTg mice were treated for 15 months with either a control diet or an isocaloric diet containing 1.5% cholesterol, and liver phenotypes and tumor-associated signaling pathways were evaluated. The high-cholesterol diet-fed HCVcpTg mice exhibited a significantly higher incidence of liver tumors compared with the control diet mice (100% vs. 41%, P < 0.001). The diet induced steatohepatitis with pericellular fibrosis and evoked higher mRNA expression of pro-inflammatory and pro-fibrotic mediators along with enhanced hepatocyte proliferation and greater oxidative and endoplasmic reticulum stress in the liver. Moreover, long-term consumption of cholesterol-rich diet activated nuclear factor-kappa B (NF-κB) and p62/sequestosome 1 (Sqstm1)-nuclear factor erythroid 2 (NRF2) axis, enhanced fibrogenesis, and consequently accelerated hepatic tumorigenesis. In conclusion, these results demonstrate that a high-cholesterol diet facilitates liver tumorigenesis by inducing steatohepatitis, promoting hepatocyte division, and up-regulating cellular stress and pro-inflammatory NF-κB and detoxifying p62/Sqstm1-NRF2 signals. Therefore, high dietary cholesterol should be avoided in HCV-infected patients to prevent development of steatohepatitis, liver fibrosis, and HCC.
先前的流行病学研究表明，高胆固醇摄入与肝脏疾病的进展有关，包括肝细胞癌（HCC）。然而，过量胆固醇摄入导致肝毒性和肝癌发生的确切机制尚不清楚。我们旨在使用丙型肝炎病毒核心基因转基因（HCVcpTg）小鼠研究饮食胆固醇的影响，这些小鼠随着年龄的增长会自发发生 HCC。雄性 HCVcpTg 小鼠用对照饮食或含有 1.5%胆固醇的等热量饮食处理 15 个月，并评估肝脏表型和肿瘤相关信号通路。与对照饮食组相比，高胆固醇饮食喂养的 HCVcpTg 小鼠的肝肿瘤发生率显著更高（100%比 41%，P<0.001）。该饮食诱导了伴有细胞周纤维化的脂肪性肝炎，并引起了促炎和促纤维化介质的 mRNA 表达升高，同时伴有肝细胞增殖增加和肝脏氧化应激和内质网应激增强。此外，长期摄入富含胆固醇的饮食激活了核因子-κB（NF-κB）和 p62/自噬相关蛋白 1（Sqstm1）-核因子红细胞 2（NRF2）轴，增强了纤维化，从而加速了肝肿瘤发生。总之，这些结果表明，高胆固醇饮食通过诱导脂肪性肝炎、促进肝细胞分裂以及上调细胞应激和促炎 NF-κB 以及解毒 p62/Sqstm1-NRF2 信号，促进肝肿瘤发生。因此，丙型肝炎病毒感染患者应避免高膳食胆固醇，以防止发生脂肪性肝炎、肝纤维化和 HCC。
