Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Aug 18, 2015; 7(17): 2110-2118
Published online Aug 18, 2015. doi: 10.4254/wjh.v7.i17.2110
Recent advances in mouse models of obesity- and nonalcoholic steatohepatitis-associated hepatocarcinogenesis
Hayato Nakagawa
Hayato Nakagawa, Department of Gastroenterology, the University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
Author contributions: Nakagawa H solely contributed to this manuscript.
Supported by Grants from the Japanese Society of Gastroenterology; The Tokyo Society of Medical Sciences; and Kanae Foundation for the Promotion of Medical Science.
Conflict-of-interest statement: The author has no conflicts of interest regarding this study.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Hayato Nakagawa, MD, PhD, Department of Gastroenterology, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Telephone: +81-3-38155411 Fax: +81-3-38140021
Received: April 7, 2015
Peer-review started: April 9, 2015
First decision: May 14, 2015
Revised: May 28, 2015
Accepted: June 30, 2015
Article in press: July 2, 2015
Published online: August 18, 2015

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and obesity has been established as a risk factor for HCC development. Nonalcoholic steatohepatitis (NASH) is apparently the key link between obesity and hepatocarcinogenesis, and obesity also accelerates HCC development synergistically with other risk factors, such as hepatitis virus infection and alcohol consumption. As an explanation for the pathogenesis of NASH, the so-called “two-hit” theory has been widely accepted, but recently, a better model, the so-called “multiple-hits hypothesis” was proposed, which states that many disease-promoting factors may occur in parallel, rather than consecutively. However, the overall mechanism remains largely unknown. Various cell-cell and organ-organ interactions are involved in the pathogenesis of NASH, and thus appropriate in vivo disease models are essential for a deeper understanding. However, replicating the full spectrum of human NASH has been difficult, as NASH involves obesity, insulin resistance, steatohepatitis, fibrosis, and ultimately HCC, and the lack of an appropriate mouse model has been a considerable barrier to determining the missing links among obesity, NASH, and HCC. In recent years, several innovative mouse models presenting obesity- and NASH-associated HCC have been established by modified diets, chemotoxic agents, genetic manipulation, or a combination of these factors, shedding some light on this complex network and providing new therapeutic strategies. Thus, in this paper, I review the mouse models of obesity- and NASH-associated HCC, especially focusing on recent advances and their clinical relevance.

Keywords: Obesity, Metabolic syndrome, Nonalcoholic steatohepatitis, Hepatocellular carcinoma, Mouse model

Core tip: Obesity is a recognized risk factor for the development of hepatocellular carcinoma (HCC) and nonalcoholic steatohepatitis (NASH), which in turn can trigger hepatocarcinogenesis. Once, no appropriate mouse model allowed exploration of the associations among obesity, NASH, and HCC, but several innovative mouse models have become established in recent years. These models have afforded new insights into the mechanisms of disease and have suggested new therapeutic strategies. Therefore, this paper reviews mouse models of obesity- and NASH-associated HCC, focusing on recent advances and clinical relevance thereof.