Cytochrome P-450 expression and activities in fatty liver diseases
(2001)
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- Fatty liver or steatosis is the commonest liver disorder and is often related to nutritional or hormonal imbalance. While considered as a benign condition, the capacity of fatty liver to respond to toxic or metabolic insult is altered. Fatty liver is believed to be the setting of a more severe and progressive disorder: nonalcoholic Steatohepatitis (NASH). This work was performed to evaluate the impact of fatty liver and NASH on liver function concentrating on the microsomal CYP system. We also aimed to explore metabolic factors that could provide insights into NASH pathogenesis. In defining tools to evaluate CYP function, we critically analysed the MEGX test and questioned its validity as a marker for liver function. We established an HPLC assay to reliably measure CYP2E1 activity in vitro and in vivo. The analyses performed on three animal models of uncomplicated fatty liver demonstrated that liver fat accumulation correlated with a profound decrease in CYP activities. This affected the major CYP families except CYP4A. Down regulation of CYP enzymes could potentially alter the metabolism of drugs in fatty liver resulting in decreased drug efficacy, enhanced Xenobiotic toxicity or increased risk of adverse effect of drug interactions in the setting of fatty liver disease. By contrast to uncomplicated fatty liver, clinical as well as experimental NASH is unambiguously associated with a selective induction of CYP2E1 together with a more general down regulation of the other CYP forms. Dietary restrictions that improve NASH, normalise CYP2E1 activity and ameliorate microsomal function. The question that arises is whether induction of CYP2E1 is a consequence or causal to the development and the progression of NASH. Several elements are in favours of the last proposition. First, acute episodes or worsening of pre-existing NASH are observed in situahons associated with CYP2E1 induction. Second, NASH clinically and morphologically mimics alcoholic Steatohepatiris disorder in which alcohol-inducible CYP2E1 is believed to play a critical role. Third, we demonstrated that, while down-regulated in uncomplicated fatty liver, the pathways for Xenobiotic and metabolic CYP2E1 induction are not impaired. The work carried out in this thesis provides evidence that injurious oxidative stress underlies the pathogenesis of NASH and probably the transition from uncomplicated forms of fatty liver to the progressive NASH. We unequivocally identify microsomal oxidases (in particular CYP2E1 and CYP4A) as catalysts of lipid peroxidation during the development of NASH. These findings are consistent with the Mtwo hits” mechanism for NASH whereby microsomal lipid peroxidation would act as an injurious process superimposed on fatty liver to initiate necroinflammatory damage and fibrosis. However, the causal links between unbalanced lipid metabolism, microsomal peroxidation, initiation of injurious oxidative stress and liver injury remain to be established. A better understanding of the factors responsible for the initiation and the perpetuation of the injurious processes in NASH is mandatory for designing rational therapies
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Leclercq, I. (2001). Cytochrome P-450 expression and activities in fatty liver diseases. https://hdl.handle.net/2078.5/110990