UMMS Affiliation

Department of Medicine, Division of Gastroenterology

Date

7-14-2014

Document Type

Article

Disciplines

Digestive System Diseases | Gastroenterology | Hepatology | Immunology and Infectious Disease

Abstract

AIM: To develop an animal model that encompasses the different facets of non-alcoholic steatohepatitis (NASH), which has been a challenge.

METHODS: In this study, we used a high fat diet (HFD) feeding supplemented with fructose and sucrose in the water mimicking the high-fructose corn syrup that is abundant in the diet in the United States. We used C57Bl/6 wild-type mice for short and long-term feedings of 6 and 16 wk respectively, and evaluated the extent of liver damage, steatosis, and inflammasome activation. Our methods included histopathological analysis to assess liver damage and steatosis, which involved H and E and oil-red-o staining; biochemical studies to look at ALT and triglyceride levels; RNA analysis using quantitative polymerase chain reaction; and cytokine analysis, which included the enzyme-linked immunosorbent assay method to look at interleukin (IL)-1beta and tumor necrosis factor-alpha (TNFalpha) levels. Furthermore, at each length of feeding we also looked at insulin resistance and glucose tolerance using insulin tolerance tests (ITT) and glucose tolerance tests.

RESULTS: There was no insulin resistance, steatosis, or inflammasome activation at 6 wk. In contrast, at 16 wk we found significant insulin resistance demonstrated by impaired glucose and ITT in male, but not female mice. In males, elevated alanine aminotransferase and triglyceride levels, indicated liver damage and steatosis, respectively. Increased liver TNFalpha and monocyte chemoattractant protein-1 mRNA and protein, correlated with steatohepatitis. The inflammasome components, adaptor molecule, Aim2, and NOD-like receptor 4, increased at the mRNA level, and functional inflammasome activation was indicated by increased caspase-1 activity and IL-1beta protein levels in male mice fed a long-term HFD. Male mice on HFD had increased alpha-smooth muscle actin and pro-collagen-1 mRNA indicating evolving fibrosis. In contrast, female mice displayed only elevated triglyceride levels, steatosis, and no fibrosis.

CONCLUSION: Our data indicate gender differences in NASH. Male mice fed a long-term HFD display steatohepatitis and inflammasome activation, whereas female mice have steatosis without inflammation.

Rights and Permissions

Citation: World J Gastroenterol. 2014 Jul 14;20(26):8525-34. doi: 10.3748/wjg.v20.i26.8525. Link to article on publisher's site

Comments

Article distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is non-commercial and is otherwise in compliance with the license.

Publisher PDF posted as allowed by the publisher's author rights policy at http://www.wjgnet.com/bpg/navdetail_51.htm

Related Resources

Link to Article in PubMed

Keywords

Gender differences, Non-alcoholic steatohepatitis, Inflammasome, High fat diet

PubMed ID

25024607

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