Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis

Abstract

Background & Aims Ethanol-inducible cytochrome P450 2E1 (CYP2E1) activity contributes to oxidative stress. However, CYP2E1 may have an important role in the pathogenesis of high-fat mediated nonalcoholic steatohepatitis (NASH). Thus, the role of CYP2E1 in high-fat mediated NASH development was evaluated. Methods Male wild-type (WT) and Cyp2e1-null mice were fed a low-fat diet (LFD, 10% energy-derived) or high-fat diet (HFD, 60% energy-derived) for 10 weeks. Liver histology and tissue homogenates were examined for various parameters of oxidative stress and inflammation. Results Liver histology showed that only WT mice fed a HFD developed NASH despite increased steatosis in both WT and Cyp2e1-null mice fed HFD. Markers of oxidative stress such as elevated CYP2E1 activity and protein amounts, lipid peroxidation, protein carbonylation, nitration, and glycation with increased phospho-JNK were all markedly elevated only in the livers of HFD-fed WT mice. Furthermore, while the levels of inflammation markers osteopontin and F4/80 were higher in HFD-fed WT mice, TNFα and MCP-1 contents were lower compared to the corresponding LFD-fed WT. Finally, only HFD-fed WT mice exhibited increased insulin resistance and impaired glucose tolerance. Conclusions These data suggest that CYP2E1 is critically important in NASH development by promoting oxidative/nitrosative stress, protein modifications, inflammation and insulin resistance.

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

“…A common denominator in the pathogenesis of NAFLD is CYP2E1-dependent oxidative stress, as a key mechanism responsible for liver damage and disease progression [62]. In our study, quercetin protects liver against NAFLD by reducing CYP2E1 overexpression and subsequent oxidative stress, in agreement with results obtained in a similar in vivo model [63].…”

NKT cell modulates NAFLD potentiation of metabolic oxidative stress-induced mesangial cell activation and proximal tubular toxicity

“…The more progressive form of NAFLD is termed NASH and is likely caused by a second or multiple hits from oxidative stress, inflammatory adipokines, activation of pattern recognition receptors, glucose intolerance, and insulin resistance (5). More recently, there have been significant studies that have shown the role of CYP2E1 in modulating the progression of NA-FLD to NASH via metabolic oxidative stress (1,21,22,30). In the present study, we used BDCM as a substrate for the generation of metabolic oxidative stress that aids in the progression of NASH (25).…”

“…NAFLD shows increased CYP2E1 induction (1). We have previously shown that metabolic oxidative stress in NA-FLD/NASH causes lipid peroxidation primarily dependent on CYP2E1 in the liver (38).…”

Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis

“…Metabolic oxidative stress in obesity-induced steatohepatitic injury is caused following increased CYP2E1 activity, mitochondrial uncoupling of the electron transport chain, or toxin metabolism following administration of hepatotoxic drugs (1,5,11,22). We and others (5,31,32) have shown that toxininduced steatohepatitis models produce metabolic oxidative stress.…”