Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis

Mohamed A Abdelmegeed,Seung-Kwon Ha,Youngshim Choi,Byoung-Joon Song,Grzegorz Godlewski,Sehwan Jang,Atrayee Banerjee

doi:10.1038/srep39764

Abstract

Cytochrome P450-2E1 (CYP2E1) increases oxidative stress. High hepatic cholesterol causes non-alcoholic steatohepatitis (NASH) and fibrosis. Thus, we aimed to study the role of CYP2E1 in promoting liver fibrosis by high cholesterol-containing fast-food (FF). Male wild-type (WT) and Cyp2e1-null mice were fed standard chow or FF for 2, 12, and 24 weeks. Various parameters of liver fibrosis and potential mechanisms such as oxidative and endoplasmic reticulum (ER) stress, inflammation, and insulin resistance (IR) were studied. Indirect calorimetry was also used to determine metabolic parameters. Liver histology showed that only WT fed FF (WT-FF) developed NASH and fibrosis. Hepatic levels of fibrosis protein markers were significantly increased in WT-FF. The nitroxidative stress marker iNOS, but not CYP2E1, was significantly elevated only in FF-fed WT. Serum endotoxin, TLR-4 levels, and inflammatory markers were highest in WT-FF. FAS, PPAR-α, PPAR-γ, and CB1-R were markedly altered in WT-FF. Electron microscopy and immunoblot analyses showed significantly higher levels of ER stress in FF-fed WT. Indirect calorimetry showed that Cyp2e1-null-mice fed FF exhibited consistently higher total energy expenditure (TEE) than their corresponding WT. These results demonstrate that CYP2E1 is important in fast food-mediated liver fibrosis by promoting nitroxidative and ER stress, endotoxemia, inflammation, IR, and low TEE.

Highlights

Nonalcoholic fatty liver disease (NAFLD) represents a hepatic metabolic syndrome[1]
Further analysis of 24 wks data by one-way ANOVA showed plasma ALT was highest in WT-FF, ALT levels in Cyp2e1-null-FF were higher than the standard rodent chow (STD)-controls (Fig. 1e)
Fat index was significantly higher in WT-FF than all other groups for all feeding periods it was significantly higher in Cyp2e1-null-FF mice than their corresponding STD-controls at 24 wks (Fig. 1i)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) represents a hepatic metabolic syndrome[1]. NAFLD includes fatty liver (simple steatosis), steatohepatitis (NASH), fibrosis, and cirrhosis[2]. By using mice fed high-fat diet (HFD) for 10 weeks (wks), we and others reported an important role of CYP2E1 in the development of NASH16,17. It is unknown whether CYP2E1 is involved in the liver fibrosis caused by HFD containing cholesterol. Critical parameters under the expanded “two hit hypothesis” were examined as potential underlying mechanism(s) to explain the differential effects between WT and Cyp2e1-null mice fed FF, i.e., by examining hepatic steatosis “the first hit” and various “second hit” factors such as oxidative stress, inflammatory response, gut-derived serum endotoxin, ER stress, and IR, which can contribute to liver fibrosis[5,6,7]. Ambulatory activities in both western FF-fed mouse strains by indirect calorimetry which may explain the different rates of body weight gain and hepatic steatosis in WT-FF and Cyp2e1-null-FF groups

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Conclusion