Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

Jian Wu

doi:10.18632/oncotarget.8641

Abstract

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver disorders with fat accumulation from simple fatty liver, nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis and NAFLD/NASH-associated hepatocellular carcinoma (HCC). NASH is a progressive form of NAFLD and requires medical attention. One of 5-10 NASH patients may progress to end-state liver disease (ESLD or cirrhosis) in 5-10 years; meanwhile, life-threatening complications of ESLD and HCC account for major mortality. An increasing burden of NAFLD in clinics, elucidation of its pathogenesis and progression, and assessment of the efficacy of potential therapeutics demand reliable animal models. Most NASH-associated HCC occurs in cirrhotic subjects; however, HCC does appear in NASH patients without cirrhosis. Lipotoxicity, oxidant stress, insulin resistance, endoplasmic reticulum stress, altered adipokine and lymphokine profiles and gut microbiome changes affect NAFLD progression and constitute key pathobiologic interplays. How these factors promote malignant transformation in a microenvironment of steatotic inflammation and fibrosis/cirrhosis, and lead to development of neoplasms is one of critical questions faced in the hepatology field. The present review summarizes the characteristics of emerging rodent NASH-HCC models, and discusses the challenges in utilizing these models to unveil the mysteries of NASH-associated HCC development.

Highlights

Nonalcoholic fatty liver disease (NAFLD) covers a wide spectrum of disorders with fat accumulation, including simple fatty liver (SFL), a progressive form of nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis and NASH-associated hepatocellular carcinoma (NASHHCC)
It is estimated that 13% of children and adolescents in the US are affected with NAFLD, and that 23% of the subjects with NAFLD have evidence of steatohepatitis and bridging fibrosis or cirrhosis was observed in 9% of the children with NASH [5]
Given the fact that a custom diet containing trans-fatty acids and high-fructose corn syrup (HFCS) plus sedentary lifestyle for 16 weeks produced a typical feature of NASH with obvious inflammation and fibrosis in mice [65], an extension of this approach to 12 months created an American lifestyleinduced obesity syndrome (ALIOS) model that accurately represents a broad similarity to the pathogenesis of human NASH and carcinoma [38]

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) covers a wide spectrum of disorders with fat accumulation, including simple fatty liver (SFL), a progressive form of nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis and NASH-associated hepatocellular carcinoma (NASHHCC). Given the fact that a custom diet containing trans-fatty acids and high-fructose corn syrup (HFCS) plus sedentary lifestyle for 16 weeks produced a typical feature of NASH with obvious inflammation and fibrosis in mice [65], an extension of this approach to 12 months created an American (sedentary) lifestyleinduced obesity syndrome (ALIOS) model that accurately represents a broad similarity to the pathogenesis of human NASH and carcinoma [38].

Results

Conclusion