Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA. Journal of Hepatology
(Impact Factor: 11.34).
06/2012; 57(4):860-6. DOI: 10.1016/j.jhep.2012.05.019
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 non-alcoholic steatohepatitis (NASH). Thus, the role of CYP2E1 in high-fat mediated NASH development was evaluated.
Male wild type (WT) and Cyp2e1-null mice were fed a low-fat diet (LFD, 10% energy-derived) or a high-fat diet (HFD, 60% energy-derived) for 10weeks. Liver histology and tissue homogenates were examined for various parameters of oxidative stress and inflammation.
Liver histology showed that only WT mice fed a HFD developed NASH despite the presence of 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 levels were lower compared to the corresponding LFD-fed WT. Finally, only HFD-fed WT mice exhibited increased insulin resistance and impaired glucose tolerance.
These data suggest that CYP2E1 is critically important in NASH development by promoting oxidative/nitrosative stress, protein modifications, inflammation, and insulin resistance.
Available from: Teresa Auguet
- "On the other hand, other studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of NASH progression. In this sense, CYP2E1, the principal isoform of the CYP450 enzyme, seems to be critically important in NASH development by promoting oxidative/nitrosative stress, protein modifications, inflammation, and IR.211,212 Moreover, Das et al suggest that purinergic receptor X7 (P2X7), upregulated by CYP2E1, might have a key role in autophagy induced by metabolic oxidative stress in NASH.213 "
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ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological change characterized by the accumulation of triglycerides in hepatocytes and has frequently been associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and insulin resistance. It is an increasingly recognized condition that has become the most common liver disorder in developed countries, affecting over one-third of the population and is associated with increased cardiovascular- and liver-related mortality. NAFLD is a spectrum of disorders, beginning as simple steatosis. In about 15% of all NAFLD cases, simple steatosis can evolve into non-alcoholic steatohepatitis, a medley of inflammation, hepatocellular injury, and fibrosis, often resulting in cirrhosis and even hepatocellular cancer. However, the molecular mechanism underlying NAFLD progression is not completely understood. Its pathogenesis has often been interpreted by the "double-hit" hypothesis. The primary insult or the "first hit" includes lipid accumulation in the liver, followed by a "second hit" in which proinflammatory mediators induce inflammation, hepatocellular injury, and fibrosis. Nowadays, a more complex model suggests that fatty acids (FAs) and their metabolites may be the true lipotoxic agents that contribute to NAFLD progression; a multiple parallel hits hypothesis has also been suggested. In NAFLD patients, insulin resistance leads to hepatic steatosis via multiple mechanisms. Despite the excess hepatic accumulation of FAs in NAFLD, it has been described that not only de novo FA synthesis is increased, but FAs are also taken up from the serum. Furthermore, a decrease in mitochondrial FA oxidation and secretion of very-low-density lipoproteins has been reported. This review discusses the molecular mechanisms that underlie the pathophysiological changes of hepatic lipid metabolism that contribute to NAFLD.
Available from: Luisa Pozzo
- "In humans and animal models of diabetes and NAFLD, the increase in circulating levels of ketone bodies and fatty acids may directly interact with CYP2E1 not only as substrates but also as inducers. Indeed, this isoform is induced in the presence of obesity , fatty liver and NASH in both humans and rodents, and its increase appears to correlate well with the severity of NAFLD (Sindhu et al., 2006; Abdelmegeed et al., 2012). Hence, it is very likely that in our model, CYP2E1 induction is due to both transcript and protein stabilization, similar to what occurs in the case of diabetes (Song et al., 1987). "
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ABSTRACT: Herein we have characterized CYPs and antioxidant enzymes in a new steatotic rat model induced with a high fat diet (HFD) combined with a low dose of streptozotocin (STZ). This model was recently put forward in order to better replicate the NAFLD human pathology. HFD/STZ rats developed hyperglycemia, hypercholesterolemia and overt steatosis. The treatment also caused liver damage, but not lipid peroxidation, suggesting this damage was due to hepatic fat deposition and excess formation of toxic free fatty acids, rather than to oxidative stress. In the HFD/STZ group, a significant rise in total CYP content was found, in conjunction with increased activity and protein levels of CYP2E1 and CYP4A, the latter also up-regulated at the transcriptional level. A significant decrease of CYP2C11 was observed at the transcriptional and protein level, whereas CYP3A2 did not change in response to HFD/STZ treatment. In our experimental conditions, the activity of the HO-1 and NQO1 enzymes, whose genes are regulated by Nrf2, were not affected, and nor were the antioxidant enzymes SOD and CAT, confirming the lack of oxidative stress. Our HFD/STZ treatment, which established overt steatosis and changes in CYPs expression, but not oxidative stress, likely reflects an early stage of NAFLD.
Available from: Mohamed A Abdelmegeed
- "The risk factors include increased nitroxidative stress, mitochondria dysfunction, insulin resistance, disturbance of fat homeostasis , gut leakage, cytokine, and immune dysregulation[103,104]. There are numerous reports in the literature showing that increased levels of iNOS, CYP2E1, and protein nitration play an important role, at least partially, in the development and/or progression of NAFLD, as shown in various experimental models and people with NASH ([74,105106107108109110111112113114115, and references therein). In a NASH model fed a HFD for 20 weeks, the overexpression of tissue inhibitor of metalloproteinase (TIMP3) in macrophages ameliorated HFD-induced insulin resistance, adipose inflammation, and NAFLD probably through the inhibition of various parameters of nitroxidative stress including hepatic protein nitration. "
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ABSTRACT: Nitric oxide, when combined with superoxide, produces peroxynitrite, which is known to be an important mediator for a number of diseases including various liver diseases. Peroxynitrite can modify tyrosine residue(s) of many proteins resulting in protein nitration, which may alter structure and function of each target protein. Various proteomics and immunological methods including mass spectrometry combined with both high pressure liquid chromatography and 2D PAGE have been employed to identify and characterize nitrated proteins from pathological tissue samples to determine their roles. However, these methods contain a few technical problems such as low efficiencies with the detection of a limited number of nitrated proteins and labor intensiveness. Therefore, a systematic approach to efficiently identify nitrated proteins and characterize their functional roles is likely to shed new insights into understanding of the mechanisms of hepatic disease pathophysiology and subsequent development of new therapeutics. The aims of this review are to briefly describe the mechanisms of hepatic diseases. In addition, we specifically describe a systematic approach to efficiently identify nitrated proteins to study their causal roles or functional consequences in promoting acute and chronic liver diseases including alcoholic and nonalcoholic fatty liver diseases. We finally discuss translational research applications by analyzing nitrated proteins in evaluating the efficacies of potentially beneficial agents to prevent or treat various diseases in the liver and other tissues.
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