Analysis and modification of the metabolic antioxidative balance as risk factor for liver fibrosis in humanized, transgenic UGT1A SNP and wild type mice
Final Report Abstract
The study was designed to evaluate the role UGT1As play in the development or prevention of liver fibrosis induced by different modes of liver injury. The initial hypothesis implies a protective effect of UGT1A enzymes based on their ability to act as indirect antioxidants. Due to an impaired metabolic antioxidative balance in SNP carriers, we hypothesized that individuals carrying a variant UGT1A-SNP haplotype are more prone to fibrosis development compared to their WT counterparts. This appears to be the case with respect to cholestatic liver diseases. Here we detected advanced fibrosis development in htgUGT1A-SNP mice likely as a result of decreased antioxidative defensive mechanisms as shown by lower peroxidase levels. As a consequence, a common haplotype observed in 10% of the white population, is more susceptible to cholestasis induced reactive metabolites capable of inflicting tissue injury leading to aggravated liver fibrosis. Coffee consumption was tested as potential strategy for therapeutically activating UGT1A transcription. Since coffee showed beneficial effects in htgUGT1A-WT and SNP mice, co-treatment can be considered as a useful tool in the treatment of cholestasis induced liver fibrosis. In the case of diet-induced steatohepatitis, a reduced catalytic activity of UGT1A proteins does not seem to have a negative effects. In contrary to the initial hypothesis, we were able to detect a protective outcome of a common UGT1A SNP haplotype associated with Gilbert syndrome leading to milder hepatic steatosis during the development of NASH. This was a highly surprising finding although these data are in agreement with protective effects that have been reported for UGT1A1 gene variants in NAFLD. To our knowledge, this is the first study providing experimental evidence for the above mentioned protection resulting in milder NASH and ameliorated liver fibrosis.
Publications
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Protective effects of coffee against oxidative stress induced by the tobacco carcinogen benzo[α]pyrene. Free Radic Biol Med. 2017 Jul;108:66-76
Kalthoff S, Landerer S, Reich J, Strassburg CP
