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

• Published in: Journal of lipid research Vol. 45; no. 6; pp. 1051 - 1060
• Main Authors: Solaas, Karianne, Kase, B. Frode, Pham, Viet, Bamberg, Krister, Hunt, Mary C., Alexson, Stefan E.H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2004; Elsevier
• Subjects: Acyltransferases - genetics; Acyltransferases - metabolism; Amides - metabolism; Animals; bile acid-coenzyme A:amino acid N-acyltransferase; bile acid-coenzyme thioesterase; Bile Acids and Salts - chemistry; Bile Acids and Salts - metabolism; Catalase - metabolism; cholestyramine; Cytosol - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Down-Regulation; farnesoid X receptor; Liver - drug effects; Liver - metabolism; Male; Medicin och hälsovetenskap; Mice; Mice, Knockout; peroxisome proliferator-activated receptor α; Peroxisomes - drug effects; Peroxisomes - enzymology; Peroxisomes - genetics; Peroxisomes - metabolism; PPAR alpha - deficiency; PPAR alpha - genetics; PPAR alpha - metabolism; Pyrimidines - pharmacology; Receptors, Cytoplasmic and Nuclear; RNA, Messenger - genetics; Subcellular Fractions - metabolism; Thiolester Hydrolases - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; cholestyramine; bile acid-coenzyme A:amino acid N-acyltransferase; bile acid-coenzyme thioesterase; farnesoid X receptor; peroxisome proliferator-activated receptor α
• DOI: 10.1194/jlr.M300291-JLR200
• ISSN: 0022-2275

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 α (PPARα). Livers from wild-type and PPARα-null mice either untreated or treated with the PPARα 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 PPARα-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 PPARα-null mice. The results from this study suggest that an increased formation of unconjugated bile acids occurs during PPARα activation.