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Papers In Press, published online ahead of print March 16, 2004
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Department of Pediatric Research, University of Oslo, Oslo NO-0027
Corresponding Author: b.f.kase{at}klinmed.uio.no
In human liver unconjugated bile acids can be formed by the action of bile acid-CoA thioesterases (BACTE), whereas bile acid conjugation with taurine or glycine (amidation)is catalyzed by bile acid-CoA:amino acid N-acyltransferases (BACAT). Both pathways exist in peroxisomes and cytosol. Bile acid amidation facilitates biliary excretion while accumulation of unconjugated bile acids may become hepatotoxic. The peroxisome proliferator-activated receptor alpha (PPARalpha) has recently been shown to regulate bile acid synthesis and secretion. Therefore we hypothesized that the formation of unconjugated and conjugated bile acids from their common substrate bile acid-CoA thioesters by BACTE and BACAT, respectively, is also regulated via PPARalpha. Livers from wild-type and PPARalpha-null mice either untreated or treated with the PPARalphaactivator WY-14,643, were analyzed for BACTE and BACAT expression. The total liver capacity of taurochenodeoxycholate and taurocholate formation was decreased in WY-14,643 treated wild type mice by 60% and 40%, respectively, but not in PPARalpha-null mice. Suppression of the peroxisomal BACAT activity was responsible for the decrease in liver capacity, while the cytosolic BACAT activity was essentially unchanged by the treatment. The decrease in peroxisomal BACAT activity was paralleled by a similar decrease in BACAT protein level. In both cytosol and peroxisomes, the BACTE activity and protein levels were up-regulated 5-10 fold by the treatment. These effects caused by WY-14,643 treatment were abolished in PPARalpha-null mice. Thus, the formation of unconjugated bile acids by BACTE and bile acid amidation by BACAT is differently regulated via PPARalpha. The results from this study suggest that an increased formation of unconjugated bile acids occurs during PPARalpha activation.
Revised on March 5, 2004
Accepted on March 8, 2004
Differential regulation of cytosolic and peroxisomal bile acid amidation in mouse liver: PPAR
activation favors formation of unconjugated bile acids
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