169 Trail Receptor Dr5-Mediated Apoptosis Signals Induce Screrosing Cholangiopathy in Mice

Abstract

culture markedly decreased nuclear LXR protein levels, suggesting that 25HC3S may complex with LXR to prevent its activation. 25HC3S administration was followed by doseand timedependent decreases in SREBP-1 protein and mRNA, consistent with down regulation of SREBP-1 transcription. 25HC3S administration also led to a decrease in mature SREBP-1 accompanied by an increase in SREBP-1 precursor, consistent with post-translational downregulation of SREBP-1 activity. 25HC3S decreased the expression of a number of SREBP1-responsive genes including acetyl CoA carboxylase-1 (ACC-1) and fatty acid synthase (FAS), key enzymes involved in fatty acid biosynthesis, as well as Cyp7A1, HMGR, and LDLR, which are key proteins involved in cholesterol metabolism. 25HC, the precursor of 25HC3S, had opposite effects, increasing SREBP-1 and FAS mRNA levels in the hepatocytes. Conclusion: 25HC3S, initially produced in mitochondria in response to excess cholesterol, is a potent down-regulator of the cholesterol and fatty acid biosynthetic pathways. The effects of 25HC3S appear to be mediated via inhibition of LXR/SREBP-1 signaling.