Original Article
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World J Gastroenterol. Jul 14, 2014; 20(26): 8525-8534
Published online Jul 14, 2014. doi: 10.3748/wjg.v20.i26.8525
High fat diet feeding results in gender specific steatohepatitis and inflammasome activation
Michal Ganz, Timea Csak, Gyongyi Szabo
Michal Ganz, Timea Csak, Gyongyi Szabo, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States
Author contributions: All the authors contributed to studying concept and design, acquisition, analysis and interpretation of data; Ganz M and Szabo G contributed to drafting of the manuscript; Csak T and Szabo G contributed to critical revision of the manuscript for important intellectual content; Szabo G contributed to obtained funding, study supervision.
Supported by National Institutes of Health Grant, No. DK075635
Correspondence to: Gyongyi Szabo, MD, PhD, Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA 01605, United States. gyongyi.szabo@umassmed.edu
Telephone: +1-508-8566113 Fax: +1-508-8564770
Received: December 18, 2012
Revised: April 11, 2013
Accepted: June 1, 2013
Published online: July 14, 2014

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)-1β and tumor necrosis factor-α (TNFα) 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 TNFα 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-1β protein levels in male mice fed a long-term HFD. Male mice on HFD had increased α-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.

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

Core tip: Our work shows that there are gender differences in the development of non-alcoholic steatohepatitis. We used a high fat diet feeding supplemented with fructose and sucrose in mice, to mimic the high-fructose corn syrup that is abundant in the western diet. There is preferential steatohepatitis and inflammasome activation in male mice, whereas female mice display steatosis without inflammation.