Solaas Karianne, Kase B Frode, Pham Viet, Bamberg Krister, Hunt Mary C, Alexson Stefan E H
Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm, Sweden.
J Lipid Res. 2004 Jun;45(6):1051-60. doi: 10.1194/jlr.M300291-JLR200. Epub 2004 Mar 16.
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 alpha (PPARalpha). Livers from wild-type and PPARalpha-null mice either untreated or treated with the PPARalpha 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 PPARalpha-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 PPARalpha-null mice. The results from this study suggest that an increased formation of unconjugated bile acids occurs during PPARalpha activation.
在人类肝脏中，未结合胆汁酸可由胆汁酸辅酶A硫酯酶（BACTEs）的作用形成，而胆汁酸与牛磺酸或甘氨酸的结合（酰胺化）则由胆汁酸辅酶A：氨基酸N - 酰基转移酶（BACATs）催化。这两条途径都存在于过氧化物酶体和细胞质中。胆汁酸酰胺化有助于胆汁排泄，而未结合胆汁酸的积累可能具有肝毒性。我们推测，BACTE和BACAT从其共同底物胆汁酸辅酶A硫酯形成未结合和结合胆汁酸的过程是通过过氧化物酶体增殖物激活受体α（PPARα）进行调节的。对未处理或用PPARα激活剂WY - 14,643处理的野生型和PPARα基因敲除小鼠的肝脏进行BACTE和BACAT表达分析。经WY - 14,643处理的野生型小鼠中，牛磺鹅去氧胆酸和牛磺胆酸形成的肝脏总能力分别降低了60%和40%，但在PPARα基因敲除小鼠中未出现这种情况。过氧化物酶体BACAT活性的抑制导致肝脏能力下降，而细胞质BACAT活性在处理后基本未变。在细胞质和过氧化物酶体中，处理使BACTE活性和蛋白质水平上调了5至10倍。PPARα基因敲除小鼠中消除了WY - 14,643处理所产生的这些影响。这项研究的结果表明，在PPARα激活过程中未结合胆汁酸的形成增加。
