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

Abstract

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. 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. The major metabolic pathway for the elimination of cholesterol from the body is its conversion to bile acids in the liver followed by excretion into bile (1Chiang J.Y.L. Regulation of bile acid synthesis.Front. Biosci. 1998; 3: d176-d193Crossref PubMed Scopus (262) Google Scholar). Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the primary bile acids synthesized in human; in addition to these bile acids, β-muricholic acid is formed in mouse liver. Before secretion into bile, the bile acids are converted to bile salts by conjugation to taurine or glycine in human and almost exclusively to taurine in mouse. The formation of bile salts serves several purposes: it greatly facilitates their secretion into bile (2Vessey D.A. Whitney J. Gollan J.L. The role of conjugation reactions in enhancing biliary secretion of bile acids.Biochem. J. 1983; 214: 923-927Crossref PubMed Scopus (31) Google Scholar), the lower pKa of bile acid conjugates prevents their precipitation in the upper intestinal environment, and it enables bile acids to act as detergents in the intestine. In addition, the amino acid conjugation is important for the detoxification of hydrophobic bile acids. The formation of bile salts is catalyzed by the bile acid-CoA:amino acid N-acyltransferase (BACAT) localized in the peroxisomes and the cytosol of liver cells (3Solaas K. Ulvestad A. Søreide O. Kase B.F. Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.J. Lipid Res. 2000; 41: 1154-1162Abstract Full Text Full Text PDF PubMed Google Scholar). The substrate for BACAT is CoA-activated bile acids, otherwise known as bile acid-CoA thioesters. They are formed within two compartments of the hepatocyte by two different mechanisms: the ATP-dependent microsomal bile acid-CoA synthetase (ligase) (BACS), and the peroxisomal β-oxidative cleavage of the 5β-cholestanoic acid side chain, the final step in bile acid synthesis (4Kase B.F. Björkhem I. Pedersen J.I. Formation of cholic acid from 3α,7α,12α-trihydroxy-5β-cholestanoic acid by rat liver peroxisomes.J. Lipid Res. 1983; 24: 1560-1567Abstract Full Text PDF PubMed Google Scholar, 5Mihalik S.J. Steinberg S.J. Pei Z. Park J. Kim D.G. Heinzer A.K. Dacremont G. Wanders R.J.A. Cuebas D.A. Smith K.D. Watkins P.A. Participation of two members of the very long-chain acyl-CoA synthetase family in bile acid synthesis and recycling.J. Biol. Chem. 2002; 277: 24771-24779Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 6Wheeler J.B. Shaw D.R. and of a rat liver bile acid from rat liver PubMed Scopus Google Scholar). These reactions are to be in the cytosolic and peroxisomal conjugation The conjugation capacity of the liver is to be very almost bile acids into bile are in liver of unconjugated bile acids in human Lipid Res. 1154-1162Abstract Full Text PDF PubMed Google Scholar). In the the bile salts are or to by intestinal is to the liver via the and bile acids are by the of the The formation of unconjugated bile acids in liver may not be in the bile, either of secretion into the bile (2Vessey D.A. Whitney J. Gollan J.L. The role of conjugation reactions in enhancing biliary secretion of bile acids.Biochem. J. 1983; 214: 923-927Crossref PubMed Scopus (31) Google or the bile acids may be in the biliary of levels of unconjugated bile acids and of the formation be in liver a by of J. of bile acids in liver by with PubMed Scopus Google Scholar, K. J. and bile acid in with biliary a with J. 1998; PubMed Scopus Google Scholar). In human liver, the levels of unconjugated bile acids and their and effects in that unconjugated bile acids are formed by cleavage of the bile acid-CoA thioesters catalyzed by the bile acid-CoA thioesterases (3Solaas K. Ulvestad A. Søreide O. Kase B.F. Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.J. Lipid Res. 2000; 41: 1154-1162Abstract Full Text Full Text PDF PubMed Google Scholar, K. Kase B.F. of an acyl-CoA that as a major of peroxisomal Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The activities of BACAT and BACTE to be in peroxisomes, and these for the bile acid-CoA thioesters formed by the peroxisomal We that an acyl-CoA in mouse liver peroxisomes, peroxisomal acyl-CoA is a major BACTE K. Kase B.F. of an acyl-CoA that as a major of peroxisomal Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). can with BACAT for the bile acid-CoA substrate in that the formation of unconjugated bile acids be in K. Kase B.F. of an acyl-CoA that as a major of peroxisomal Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). is for a the cytosolic BACAT and BACTE activities for the bile acid-CoA thioesters formed by the microsomal synthetase (3Solaas K. Ulvestad A. Søreide O. Kase B.F. Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.J. Lipid Res. 2000; 41: 1154-1162Abstract Full Text Full Text PDF PubMed Google Scholar, K. Søreide O. Kase B.F. of and activity in human J. 2000; PubMed Scopus Google Scholar). In and that the of bile acid bile formation levels of unconjugated hydrophobic bile acids or liver of the effects of bile acids and synthesis by rat in primary 2000; Scholar, conjugation of bile acids human cells in Biol. PubMed Scopus Google Scholar, A. A. G. A. of bile salts biliary a study in bile and rat PubMed Scopus Google Scholar, of bile acids hepatocyte or 2002; PubMed Scopus Google Scholar, G. of acids an PubMed Scopus Google Scholar). levels of unconjugated bile acids, are to be important for cholesterol by as for the receptor the bile receptor G. J.B. Bile for an PubMed Scopus Google Scholar, receptor to bile acids and cholesterol Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (262) Google Scholar, J. K. bile acids are for the receptor 3: Full Text Full Text PDF PubMed Scopus Google Scholar, G. of the receptor bile acid and 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. K.D. of a receptor for bile PubMed Scopus Google Scholar). to be the activator of in followed by acid and acid whereas by bile acids and the of bile acid BACAT and were to be upregulated by the and in rat liver were in the of the and in the of the BACAT for an of bile acid amidation J.L. receptor bile acid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the peroxisome proliferator-activated receptor α was to the of cholesterol and bile acid secretion bile acid synthesis via peroxisome proliferator-activated of cholesterol and Biol. PubMed Scopus Google and to bile acid by regulating the of the G. The peroxisome proliferator-activated receptor bile acid Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). a study of the of the formation of unconjugated and conjugated bile acids from their common the bile acid-CoA via In mouse liver, the and activity of the peroxisomal and cytosolic BACAT are regulated by may for the liver of bile acids and secretion into and were synthesized by the of of bile PubMed Scopus Google and by a and were from and were from WY-14,643 was from and were from were of to wild-type and PPARα-null mice of a from the of J. of the of the peroxisome proliferator-activated receptor in mice results in of the effects of peroxisome Biol. PubMed Scopus Google were this The mice were in a and and were a of the treatment. The mice were treated with a either of the PPARα WY-14,643 or for mice to the of the the mice were by followed by The liver were and either and in a for or in and were from or wild-type and PPARα-null mouse liver as K. Kase B.F. Björkhem I. Pedersen J.I. Formation of chenodeoxycholic acid from acid by rat liver peroxisomes.J. Lipid Res. Full Text PDF PubMed Google Scholar). liver from of untreated wild-type mice or WY-14,643-treated wild-type mice were into and cytosolic as (3Solaas K. Ulvestad A. Søreide O. Kase B.F. Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.J. Lipid Res. 2000; 41: 1154-1162Abstract Full Text Full Text PDF PubMed Google Scholar). of the were of and for in a of were from the of the the the activities were for of of of rat liver and PubMed Scopus Google Scholar), the microsomal A. J. study of and from rat liver. of the microsomal by and in Biol. PubMed Scopus Google Scholar), the peroxisomal of acid and in J. PubMed Scopus Google Scholar), and the cytosolic R.J.A. G. of peroxisomal and of in Res. PubMed Scopus Google Scholar). was by the of and for the of of protein the of PubMed Scopus Google Scholar). BACAT (3Solaas K. Ulvestad A. Søreide O. Kase B.F. Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.J. Lipid Res. 2000; 41: 1154-1162Abstract Full Text Full Text PDF PubMed Google and BACTE K. Kase B.F. of an acyl-CoA that as a major of peroxisomal Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google activities were as the mouse BACAT amino acid and of mouse liver bile acid acid Lipid Res. Full Text PDF PubMed Google Scholar), a with the a the for of the was synthesized and to in The of this with BACAT was by human BACAT protein and from was in a to the of the K. acyl-CoA thioesterases a family in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google by Both were from was in as of the peroxisome proliferator-activated receptor in regulating long-chain acyl-CoA Lipid Res. 2000; 41: Full Text Full Text PDF PubMed Google of protein by followed by to The were in and for with the BACAT in in and for with in the with the was The were to and was The was to and with the as was from mouse the total and was as of the peroxisome proliferator-activated receptor in regulating long-chain acyl-CoA Lipid Res. 2000; 41: Full Text Full Text PDF PubMed Google Scholar). The were with a for mouse BACAT and of mouse liver bile acid acid Lipid Res. Full Text PDF PubMed Google and a for The were to and were the The of human acids was in as an protein the and the protein was by The activity of human was in an and were from from receptor was as human receptor and the activity was in the of in the the addition of were for and was in a was and was and were by the by the and the by were by results are the that PPARα the final in bile the bile acid amidation BACAT activity in liver from untreated and WY-14,643-treated wild-type and PPARα-null mice. The activity of taurine conjugation with was decreased to in the WY-14,643-treated wild-type mouse liver with untreated wild-type mice results were for taurine conjugation with not In untreated PPARα-null the BACAT activity was that in untreated wild-type mice but was by treatment with WY-14,643 In a study liver the of BACAT activity was not In wild-type the liver increased WY-14,643 treatment from to and a was in PPARα-null from to In untreated wild-type the total liver activity of taurochenodeoxycholate formation was with a total activity of for the WY-14,643-treated mice. in of the caused by PPARα the total capacity to was decreased by The for total taurocholate formation were in untreated mice and for the WY-14,643-treated mice. The liver were into were into in and cytosolic and of these was by the of BACAT and BACTE with WY-14,643 in a decrease in the activity of taurochenodeoxycholate formation in whereas the activity essentially unchanged in the cytosolic In activity was increased in the a of peroxisome and in the cytosolic of the total BACAT activity was in the and was in the cytosolic of mice with WY-14,643 the that was in the and was in the cytosolic that the BACAT activity is in the peroxisomal of rat and human liver (3Solaas K. Ulvestad A. Søreide O. Kase B.F. Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.J. Lipid Res. 2000; 41: 1154-1162Abstract Full Text Full Text PDF PubMed Google Scholar, B.F. Björkhem I. bile N-acyltransferase in rat Biol. Chem. Full Text PDF PubMed Google Scholar). peroxisomes are in the of BACAT activity in these by WY-14,643 treatment is to of the peroxisomal BACAT expression. The in peroxisomes, were to BACAT activity and protein were in that the BACAT activity was localized to the peroxisomal The BACAT activity decreased by in the peroxisomal WY-14,643 treatment whereas activity was decreased by The in the of activity from to peroxisomes from and WY-14,643 treated mice is to a very in the of peroxisomes in the treatment with WY-14,643 with the of peroxisomes in the from untreated mice. the decrease in BACAT activity in the peroxisomal was to a decrease in BACAT the were analyzed by a that BACAT The BACAT protein was as an protein in the and peroxisomal In with the activity a 10-fold decrease in BACAT protein was in the peroxisomal treatment with WY-14,643 whereas cytosolic liver BACAT protein unchanged by the treatment. a the was and with a the of to be upregulated by treatment K. acyl-CoA thioesterases a family in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In to the of was increased in the and peroxisomal in to WY-14,643 treatment in BACAT protein levels by the BACAT with in the activities of BACAT in the in activities of BACAT and in treatment with from of from untreated mice and from WY-14,643-treated mice were and analyzed as in and The are of taurochenodeoxycholate formation and activity in microsomal cytosolic of but not BACAT activity and protein levels treatment with peroxisomes were by of from of from untreated and WY-14,643-treated mice. Formation of taurochenodeoxycholate was in by as in and activity in cytosolic and peroxisomal of BACAT protein and a BACAT primary as in and of BACAT protein in of peroxisomal protein and of protein from the cytosolic and were for The in the was and with an peroxisomal acyl-CoA of but not BACAT activity and protein levels treatment with peroxisomes were by of from of from untreated and WY-14,643-treated mice. Formation of taurochenodeoxycholate was in by as in and activity in cytosolic and peroxisomal of BACAT protein and a BACAT primary as in and of BACAT protein in of peroxisomal protein and of protein from the cytosolic and were for The in the was and with an peroxisomal acyl-CoA of but not BACAT activity and protein levels treatment with peroxisomes were by of from of from untreated and WY-14,643-treated mice. Formation of taurochenodeoxycholate was in by as in and activity in cytosolic and peroxisomal of BACAT protein and a BACAT primary as in and of BACAT protein in of peroxisomal protein and of protein from the cytosolic and were for The in the was and with an peroxisomal acyl-CoA The PPARα in the of BACAT was by a mouse BACAT two of and were and of the major of a treatment of wild-type mice with WY-14,643 In untreated PPARα-null BACAT levels were lower in wild-type mice and the unchanged WY-14,643 treatment BACAT levels treatment of mice with WY-14,643 and was of liver total from untreated and WY-14,643-treated wild-type and PPARα-null mice mouse BACAT as The for the of mouse BACAT was to the for in and the for the of untreated wild-type mice was to The are of untreated and WY-14,643-treated wild-type mice is to the was of liver total from of untreated and wild-type and PPARα-null mice mouse BACAT as The for BACAT was to in The are treatment bile acids in the and results in a of bile acid biosynthesis Bile acid and cholesterol in the mouse as by Biol. PubMed Scopus Google Scholar, of bile acid in PubMed Scopus Google Scholar). analyzed the of the cytosolic BACAT treatment. The results that BACAT levels increased by to treatment with in both wild-type mice and PPARα-null mice We that the activity of BACTE was increased in liver by WY-14,643 treatment of wild-type but the activity unchanged by treatment of the PPARα-null mice K. Kase B.F. of an acyl-CoA that as a major of peroxisomal Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). the of WY-14,643 treatment BACTE activity in the liver for the BACAT activity were for the BACTE activity The activity of BACTE was to be increased by WY-14,643 treatment in the and microsomal was in the In the cytosolic the activity was and the activity was increased not in WY-14,643-treated with untreated wild-type mice. In the the were and to WY-14,643 treatment of mice results in and total liver protein in the and cytosolic were with the from of untreated to an in the total liver activity of cytosolic BACTE and an the total activity in the The in the was to a 5- to of the BACTE activity in the peroxisomal PPARα the of peroxisomal BACAT protein the of the cytosolic BACAT essentially BACTE activity is increased in both peroxisomes and may decreased bile acid amidation and increased formation of unconjugated bile acids in the liver. acids act as for the PPARα acids and with peroxisome proliferator-activated α and PubMed Scopus Google Scholar, J. acids, and are for peroxisome proliferator-activated α and PubMed Scopus Google Scholar), whereas the thioesters act as I. I. J. K. the effects of peroxisome proliferator-activated receptor and with Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Both bile acids and bile salts to be for G. J.B. Bile for an PubMed Scopus Google Scholar, receptor to bile acids and cholesterol Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (262) Google Scholar, J. K. bile acids are for the receptor 3: Full Text Full Text PDF PubMed Scopus Google Scholar, G. of the receptor bile acid and 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. K.D. of a receptor for bile PubMed Scopus Google Scholar). the that bile acid-CoA thioesters may act as for a and were to the receptor by to The of was In this as an with an of whereas the was the with an of as a whereas was not to a to an of of the bile acid-CoA thioesters the of the of receptor to that are not for the in this study that treatment with WY-14,643 the total liver bile acid amidation activity in whereas BACTE activity was both effects PPARα The was that the decreased liver bile acid amidation activity was to a decrease in peroxisomal whereas the activity essentially unchanged in the cytosolic is the that both activities are in peroxisomes and cytosol of mouse liver, to the in rat and human liver (3Solaas K. Ulvestad A. Søreide O. Kase B.F. Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.J. Lipid Res. 2000; 41: 1154-1162Abstract Full Text Full Text PDF PubMed Google Scholar, K. Søreide O. Kase B.F. of and activity in human J. 2000; PubMed Scopus Google Scholar, B.F. Björkhem I. bile N-acyltransferase in rat Biol. Chem. Full Text PDF PubMed Google Scholar). of the that both BACAT activity and protein were decreased 10-fold in the peroxisomes by WY-14,643 whereas activity and protein essentially unchanged in the cytosolic The for the in BACAT levels and activity is not that the BACAT is localized in the cytosol J. The human bile acid-CoA:amino acid N-acyltransferase in the conjugation of acids to Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the of a BACAT is in the that is for this was by and J. is a of bile acid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), that the BACAT is of the hepatocyte They that in of essentially levels of BACAT in of the bile acids in bile were with an in glycine In to BACTE activity was upregulated in both cytosol and peroxisomes by WY-14,643 treatment. The of the activity was essentially the for both bile acid-CoA in The in this study to BACAT activity to that the decrease in BACAT activity not be to for substrate by BACTE in in it is that BACTE and BACAT for the common bile acid-CoA BACAT different in cytosol and peroxisomes, as in a human was that is localized in the and bile acids and to the whereas the human peroxisomal very long-chain acyl-CoA synthetase 3α,7α,12α-trihydroxy-5β-cholestanoic acid to S.J. Steinberg S.J. Pei Z. Park J. Kim D.G. Heinzer A.K. Dacremont G. Wanders R.J.A. Cuebas D.A. Smith K.D. Watkins P.A. Participation of two members of the very long-chain acyl-CoA synthetase family in bile acid synthesis and recycling.J. Biol. Chem. 2002; 277: 24771-24779Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). is that the peroxisomal synthetase peroxisomal β-oxidative side cleavage of and to synthesized bile to in peroxisomes B.F. Pedersen J.I. Björkhem I. In and in formation of bile acids in with that peroxisomes are of in the biosynthesis of both cholic and chenodeoxycholic PubMed Scopus Google Scholar). and formed by peroxisomal are the for peroxisomal BACAT excretion into bile B.F. Björkhem I. bile N-acyltransferase in rat Biol. Chem. Full Text PDF PubMed Google Scholar). the very of peroxisomal BACAT in with an of BACTE the of amidation of synthesized bile acids that formed and thioesters from peroxisomal are converted to unconjugated bile acids the of bile formation by PPARα as in of amidation by the microsomal and cytosolic BACAT of synthesized bile acids is is the in the of both bile acids from the and formed bile acids from the peroxisomes its capacity, in the accumulation of unconjugated bile acids in liver the of that peroxisomal BACAT is by WY-14,643 treatment of mice is the the of a peroxisomal via The by the of the peroxisomal BACAT is is not but it may by PPARα and for to the a to several in bile acid synthesis are regulated via and activity are in and mice by treatment with and to bile acid excretion bile acid synthesis via peroxisome proliferator-activated of cholesterol and Biol. PubMed Scopus Google Scholar, A. of and of cholesterol and in PubMed Scopus Google Scholar, A. of different of and of treatment with acid the of cholesterol in Biol. PubMed Scopus Google Scholar, K. of cholesterol in activity of cholesterol Google Scholar). PPARα to the of and bile acid G. The peroxisome proliferator-activated receptor bile acid Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The human bile is in and was to be regulated via PPARα in may to the decreased bile excretion during PPARα bile is regulated by the peroxisome proliferator-activated receptor Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The of decreased bile acid amidation are not that PPARα decreased bile acid amidation in to WY-14,643 treatment is in with an decrease in bile acid synthesis and with of increased of BACTE in cytosol and peroxisomes, it is that PPARα decreased amidation of synthesized bile acids, and of bile acids, to an in bile acids in mouse liver. PPARα to the accumulation of bile acids in liver be by levels of bile acids and bile of biliary bile acids may not levels of unconjugated bile acids of secretion into the bile In with biliary the accumulation of unconjugated bile acids to of total bile was in liver whereas were in their K. J. and bile acid in with biliary a with J. 1998; PubMed Scopus Google Scholar). be with liver to the that unconjugated hydrophobic bile acids may be to the liver of this a was that treatment of BACAT and cytosolic BACAT protein and activity by liver bile acid acid and peroxisomal Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). The for the different in rat and mouse is not but it be to the that a and may different of of BACAT is upregulated via the in rat but not in mouse J.L. receptor bile acid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), a rat and mouse in the of the BACAT Bile acid the of and bile acid treatment with a that of bile acids, and bile acid These effects are via for bile acids and bile salts are or G. J.B. Bile for an PubMed Scopus Google Scholar, J. K. bile acids are for the receptor 3: Full Text Full Text PDF PubMed Scopus Google Scholar, A. K.D. of a receptor for bile PubMed Scopus Google Scholar). In an to the of increased synthesis of bile acids BACAT treated mice with to in BACAT levels was as a of treatment in both wild-type and PPARα-null mice. In treatment of mice with BACAT not in with by J.L. receptor bile acid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. is a of bile acid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These and bile acid treatment suggest that bile acids not BACAT via but via in mice. In of that thioesters of acids may act as for PPARα I. I. J. K. the effects of peroxisome proliferator-activated receptor and with Biol. Chem. Full Text Full Text PDF PubMed Scopus Google whereas acids are for PPARα acids and with peroxisome proliferator-activated α and PubMed Scopus Google Scholar, J. acids, and are for peroxisome proliferator-activated α and PubMed Scopus Google Scholar), the that bile acid-CoA thioesters act as for an bile acid-CoA thioesters were to of the was the followed by whereas was to be a very The of that thioesters of bile acids may act as for is not in of the of the bile acid amidation activity and of BACTE may the of and bile acids as as levels of bile PPARα may to PPARα and is by that bile acids can the action of PPARα of the of peroxisome proliferator-activated by bile Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and that bile acids can the of the human PPARα via I. Bile acids the of the human peroxisome proliferator-activated receptor via of the PubMed Scopus Google Scholar). In this study that PPARα in mice decreased the peroxisomal capacity to bile acids and upregulated both peroxisomal and cytosolic BACTE These effects are to decrease bile acid amidation in metabolic PPARα and PPARα may an accumulation of unconjugated bile acids in liver and or liver The for and J. and for the PPARα-null mice. and of the human was by the in The for the of BACAT was by from the K. the and the and bile acid-CoA:amino acid N-acyltransferase bile acid-CoA synthetase bile acid-CoA cholic acid chenodeoxycholic acid receptor hepatocyte acid peroxisome proliferator-activated receptor α peroxisomal acyl-CoA 3α,7α,12α-trihydroxy-5β-cholestanoic acid