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Journal of Lipid Research, Vol. 45, 1051-1060, June 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Differential regulation of cytosolic and peroxisomal bile acid amidation by PPAR activation favors the formation of unconjugated bile acids

Karianne Solaas^*, B. Frode Kase^1,, Viet Pham, Krister Bamberg, Mary C. Hunt^* and Stefan E. H. Alexson^*

^* Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm, Sweden
Department of Pediatric Research, Rikshospitalet, NO-0027 Oslo, Norway
Department of Molecular Biology, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden

¹ To whom correspondence should be addressed. e-mail: b.f.kase{at}klinmed.uio.no

In human liver, unconjugated bile acids can be formed by the action of bile acid-CoA thioesterases (BACTEs), whereas bile acid conjugation with taurine or glycine (amidation) is catalyzed by bile acid-CoA:amino acid N-acyltransferases (BACATs). Both pathways exist in peroxisomes and cytosol. Bile acid amidation facilitates biliary excretion, whereas the accumulation of unconjugated bile acids may become hepatotoxic. We hypothesized that the formation of unconjugated and conjugated bile acids from their common substrate bile acid-CoA thioesters by BACTE and BACAT is regulated via the peroxisome proliferator-activated receptor (PPAR). Livers from wild-type and PPAR-null mice either untreated or treated with the PPAR activator 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 PPAR-null mice. Suppression of the peroxisomal BACAT activity was responsible for the decrease in liver capacity, whereas cytosolic BACAT activity was essentially unchanged by the treatment. In both cytosol and peroxisomes, the BACTE activities and protein levels were upregulated 5- to 10-fold by the treatment. These effects caused by WY-14,643 treatment were abolished in PPAR-null mice.

The results from this study suggest that an increased formation of unconjugated bile acids occurs during PPAR activation.

Abbreviations: BACAT, bile acid-CoA:amino acid N-acyltransferase; BACS, bile acid-CoA synthetase; BACTE, bile acid-CoA thioesterase; CA, cholic acid; CDCA, chenodeoxycholic acid; FXR, farnesoid X receptor; HNF-4, hepatocyte nuclear factor 4; LCA, lithocholic acid; PPAR, peroxisome proliferator-activated receptor ; PTE-2, peroxisomal acyl-CoA thioesterase 2; THCA, 3,7,12-trihydroxy-5ß-cholestanoic acid

Supplementary key words bile acid-coenzyme A:amino acid N-acyltransferase • bile acid-coenzyme thioesterase • peroxisome proliferator-activated receptor • farnesoid X receptor • cholestyramine

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