reported the effect of leptin on constitutive levels of CYP2E1 mRNA in ob/ob mice, although Hnf1α expression was not determined.7 CYP2E1 protein and activity are induced by its substrates such as acetone, ethanol, and fatty acids. In vivo studies suggested that the CYP2E1 protein can be stabilized by the presence of its substrates, which interrupt the rapid turnover component of enzyme expression. CYP2E1 degradation can occur via both lysosome fusion with endoplasmic reticulum and the ubiquitin-independent proteosomal

pathway. In the presence of substrate, CYP2E1 might not be subjected to the more rapid phase of proteasomal degradation because of altered conformation of the protein as a result of substrate binding, or preferential sequestration of the enzyme in certain regions of the endoplasmic reticulum.8,9 Meanwhile, click here in vitro study based on cultured cell lines HepG2 and rat FaO hepatocellular

carcinoma cells that do not have an extensive endoplasmic reticulum network showed that electron transfer actually increases proteosomal degradation of CYP2E1.8,10 CYP2E1 also demonstrates mRNA stabilization, which is associated with the elevation of CYP2E1 during fasting.11 Such stabilization of the CYP2E1 mRNA is reversed by insulin,12 as Truong et al. revealed the presence of a 16-nucleotide sequence in the 5′ region of the CYP2E1 mRNA that is responsible for insulin-mediated destabilization of the mRNA.13 In this issue of the Journal of Gastroenterology and Hepatology, Ethirvel and colleagues demonstrate that transgenic mice overexpressing CYP2E1 Dinaciclib price developed severer experimental steatohepatitis than non-transgenic control mice.14 Overexpression of CYP2E1 correlated with upregulation of antioxidant enzymes, including check details superoxide dismutase (SOD), catalase (CAT), glutathione

peroxidase (GPx) and heme oxygenase-1 (HO-1) at the mRNA level, presumably in response to increased oxidative stress. This negative feedback mechanism is known to be mediated through the transcription factor nuclear related factor 2 (Nrf-2). However, the protein level and activity of these enzymes did not increase accordingly, except HO-1, an important antioxidant defense enzyme in the development of steatohepatitis.15 Upregulation of HO-1 and other antioxidant enzymes may be an important adaptive response against the increased oxidative stress produced by CYP2E1 overexpression. The unchanged protein expression of SOD, CAT and GPx could possibly be due to protein degradation as a result of nitrosylation of tyrosine residues. Clarification of these issues would be very helpful in answering the question of whether and which antioxidant enzymes are of potentially benefit in designing therapeutic intervention for NASH. Although CYP2E1 plays a crucial role in inducing oxidative stress, it is not an essential requirement. Leclercq et al.