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Engineering >> 2021, Volume 7, Issue 12 doi: 10.1016/j.eng.2021.08.019

Mechanisms of Steatosis-Derived Hepatocarcinogenesis: Lessons from HCV Core Gene Transgenic Mice

a Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
b State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
c Department of Gastroenterology, Lishui Hospital, Zhejiang University School of Medicine, Lishui 323000, China
d Department of Pathophysiology, Hebei Medical University, Shijiazhuang 050017, China
e Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
f Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Bethesda, MD, 20892, United States
g Department of Infection Control and Prevention, The University of Tokyo, Tokyo 113-0033, Japan
h Department of Gastroenterology, The University of Tokyo, Tokyo 113-0033, Japan
i International Relations Office, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
j Research Center for Social Systems, Shinshu University, Matsumoto 390-8621, Japan

Received: 2020-12-12 Revised: 2021-07-22 Accepted: 2021-08-09 Available online: 2021-10-26

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Abstract

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) worldwide. Among the structural proteins of HCV, the HCV core protein has the ability to regulate gene transcription, lipid metabolism, cell proliferation, apoptosis, and autophagy, all of which are closely related to the development of HCC. Transgenic mice carrying the HCV core gene exhibited age-dependent insulin resistance, hepatic steatosis, and HCC that resembled the clinical characteristics of chronic hepatitis C patients. Several dietary modifications, including calorie restriction and diets rich in saturated fatty acids (SFAs), trans fatty acids (TFAs), or cholesterol, were found to influence hepatic steatogenesis and tumorigenesis in HCV core gene transgenic mice. These strategies modulated hepatocellular stress and proliferation, in addition to hepatic fibrotic processes and the microenvironment, thereby corroborating a close interconnection between dietary habits and steatosis-related hepatocarcinogenesis. In this review, we summarize the findings obtained from mouse models transgenic for the HCV genome, with a special focus on HCV core gene transgenic mice, and discuss the mechanisms of steatogenesis and hepatocarcinogenesis induced by the HCV core protein and the impact of dietary habits on steatosis-derived HCC development.

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