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American Journal of Physiology-Gastrointestinal and Liver Physiology

29-07-2019

Authors
Maximilian Joseph Brol, Felicitas Rösch, Robert Schierwagen, Fernando Magdaleno, Frank Erhard Uschner, Steffen Manekeller, Alexander Queck, Katharina Schwarzkopf, Margarete Odenthal, Uta Drebber, Maja Thiele, Philipp Lingohr, Andreas Plamper, Glen Kristiansen, Sophie Lotersztajn, Aleksander Krag, Sabine Klein, Karl P. Rheinwalt, and Jonel Trebicka

Abstract
Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis, steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection (n = 7), NAFLD (n = 8), or ALD (n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steatohepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing.

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