Abstract
BackgroundThe incidence of hepatocellular carcinoma with nonalcoholic steatohepatitis is increasing, and its clinicopathological features are well established. Several animal models of nonalcoholic steatohepatitis have been developed to facilitate its study; however, few fully recapitulate all its clinical features, which include insulin resistance, inflammation, fibrosis, and carcinogenesis. Moreover, these models require a relatively long time to produce hepatocellular carcinoma reliably. The aim of this study was to develop a mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis that develops quickly and reflects all clinically relevant features.MethodsThree-week-old C57BL/6J male mice were fed either a standard diet (MF) or a choline-deficient, high-fat diet (HFCD). The mice in the MF + diethylnitrosamine (DEN) and HFCD + DEN groups received a one-time intraperitoneal injection of DEN at the start of the respective feeding protocols.ResultsThe mice in the HFCD and HFCD + DEN groups developed obesity early in the experiment and insulin resistance after 12 weeks. Triglyceride levels peaked at 8 weeks for all four groups and decreased thereafter. Alanine aminotransferase levels increased every 4 weeks, with the HFCD and HFCD + DEN groups showing remarkably high levels; the HFCD + DEN group presented the highest incidence of nonalcoholic steatohepatitis. The levels of fibrosis and steatosis varied, but they tended to increase every 4 weeks in the HFCD and HFCD + DEN groups. Computed tomography scans indicated that all the HFCD + DEN mice developed hepatic tumors from 20 weeks, some of which were glutamine synthetase-positive.ConclusionsThe nonalcoholic steatohepatitis-hepatocellular carcinoma model we describe here is simple to establish, results in rapid tumor formation, and recapitulates most of the key features of nonalcoholic steatohepatitis. It could therefore facilitate further studies of the development, oncogenic potential, diagnosis, and treatment of this condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-016-0477-5) contains supplementary material, which is available to authorized users.
Highlights
The incidence of hepatocellular carcinoma with nonalcoholic steatohepatitis is increasing, and its clinicopathological features are well established
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and carcinogenesis [4]
By feeding C57BL/6 mice an HFCD combined with DEN exposure, we developed a novel experimental NASH-hepatocellular carcinoma (HCC) mouse model that exhibits all the relevant clinical features by 20 weeks, including insulin resistance, inflammation, fibrosis, and carcinogenesis
Summary
The incidence of hepatocellular carcinoma with nonalcoholic steatohepatitis is increasing, and its clinicopathological features are well established. Several animal models of nonalcoholic steatohepatitis have been developed to facilitate its study; few fully recapitulate all its clinical features, which include insulin resistance, inflammation, fibrosis, and carcinogenesis. These models require a relatively long time to produce hepatocellular carcinoma reliably. The aim of this study was to develop a mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis that develops quickly and reflects all clinically relevant features. In accordance with multiple-hit theory, metabolic syndrome, genetic factors, oxidative stress, inflammatory cytokines, endotoxins, and insulin resistance have been shown to be involved in NASH development and the progression of NASH-HCC [5]. A number of studies describing the natural history of NASH have found liver failure and HCC to be the major causes of death [6,7,8,9,10,11,12]
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