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      Animal Models of Nonalcoholic Fatty Liver Disease—A Starter’s Guide

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          Abstract

          Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a prevalence of up to 30% in the general population. Animal models have played a vital role in elucidating the pathophysiological mechanisms of NAFLD and continue to do so. A myriad of different models exists, each with its advantages and disadvantages. This review presents a brief overview of these models with a particular focus on the basic mechanisms and physical, biochemical and histological phenotype. Both nutritional and chemically induced, as well as genetic models are examined, including models combining different approaches.

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          Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.

          Yasuo Horie, Akira Suzuki, Ei Kataoka … (2004)
          PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePten(flox/flox) mice). AlbCrePten(flox/flox) mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and beta-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARgamma and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePten(flox/flox) livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePten(flox/flox) livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePten(flox/flox) mice also showed insulin hypersensitivity. In vitro, AlbCrePten(flox/flox) hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.
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            Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin.

            Ina Bergheim, Synia Weber, Miriam B Vos … (2008)
            Consumption of refined carbohydrates in soft drinks has been postulated to be a key factor in the development of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to test the effects of ad libitum access to different sugars consumed in drinking water on hepatic fat accumulation. For 8 weeks, C57BL/J6 mice had free access to solutions containing 30% glucose, fructose, sucrose, or water sweetened with artificial sweetener (AS) or plain water. Body weight, caloric intake, hepatic steatosis and lipid peroxidation were assessed. Total caloric intake and weight gain were highest in mice exposed to glucose. In contrast, hepatic lipid accumulation was significantly higher in mice consuming fructose compared to all other groups. Moreover, endotoxin levels in portal blood and lipid peroxidation as well as TNFalpha expression were significantly higher in fructose fed mice than in all other groups. Concomitant treatment of fructose fed mice with antibiotics (e.g., polymyxin B and neomycin) markedly reduced hepatic lipid accumulation in fructose fed mice. These data support the hypothesis that high fructose consumption may not only lead to liver damage through overfeeding but also may be directly pro-inflammatory by increasing intestinal translocation of endotoxin.
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              Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

              Yoshihisa Takahashi, Yurie Soejima, Toshio Fukusato (2012)
              Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nutrients
                Journal ID (iso-abbrev): Nutrients
                Journal ID (publisher-id): nutrients
                Title: Nutrients
                Publisher: MDPI
                ISSN (Electronic): 2072-6643
                Publication date (Electronic): 27 September 2017
                Publication date Collection: October 2017
                Volume: 9
                Issue: 10
                Electronic Location Identifier: 1072
                Affiliations
                [1 ]Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, 2610 Antwerp, Belgium
                [2 ]Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2650 Edegem, Belgium; luisa.vonghia@ 123456uza.be (L.V.); sven.francque@ 123456uza.be (S.M.F.)
                Author notes
                [* ]Correspondence: mikhail.vanherck@ 123456uantwerpen.be ; Tel.: +32-3-265-25-89
                Author information
                https://orcid.org/0000-0002-0531-6667
                Article
                Publisher ID: nutrients-09-01072
                DOI: 10.3390/nu9101072
                PMC ID: 5691689
                PubMed ID: 28953222
                SO-VID: e841538d-8e52-4513-8f9a-7ff36f429955
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 15 August 2017
                Date accepted : 25 September 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,animal model,mouse,rat,hepatocellular carcinoma,high-fat diet,fibrosis
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, animal model, mouse, rat, hepatocellular carcinoma, high-fat diet, fibrosis

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