Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26.
Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26.
复制标题
脑腱黄瘤病中胆汁酸的生物合成。
DOI：
10.1172/jci112030
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发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Batta,AK
中科院分区：
文献类型：
--
作者：
Salen,G;Shefer,S;Tint,GS;Nicolau,G;Dayal,B;Batta,AK
为了检查侧链氧化的缺陷，在形成胆汁酸的肌腱黄瘤病，我们测量了体外肝微粒体羟基化在C-12和C-25和线粒体羟基化在C-26和相关的池大小和合成率的胆酸和鹅去氧胆酸的同位素稀释技术确定。肝微粒体和线粒体的制备从七个受试者与肌腱黄瘤病和五个对照。在腱性黄瘤病中，初级胆汁酸合成显著减少，如下所示：胆酸，133 +/- 30 vs.对照组260 +/- 60 mg/d;鹅去氧胆酸，22 +/- 10 vs.对照组150 +/- 30 mg/d。根据鹅去氧胆酸合成的假设，所有标本中均存在5 β-胆甾烷-3 α，7 α-二醇的线粒体26-羟基化，其活性是相应微粒体25-羟基化的30倍。然而，5 β-胆甾烷-3 α，7 α-二醇的平均线粒体26-羟基化在腱性黄瘤病中的活性低于对照组：59 +/- 17与126 +/- 21 pmol/mg蛋白/min相比。至于胆酸合成，5 β-胆甾烷-3 α，7 α，12 α-三醇在肌腱黄瘤病和对照制剂中显著较高（620 +/-103和515 +/-64 pmol/mg蛋白质/min，分别）比相同底物的相应对照线粒体26-羟基化（165 +/-25 pmol/mg蛋白质/min）。此外，在腱性黄瘤病中，线粒体5 β-胆甾烷-3 α，7 α，12 α-三醇-26-羟化酶活性是对照组的七分之一。肝微粒体12 α-羟基化可能是胆酸途径的速率控制，在腱性黄瘤病中的活性是对照组的3倍：1,600 vs. 500 pmol/这些结果表明，在腱性黄瘤病中，初级胆汁酸的合成受到严重抑制，鹅去氧胆酸的形成减少，并且池的大小不成比例地大于胆酸的形成。酸鹅去氧胆酸缺乏可通过过度活跃的微粒体12 α-羟基化（将前体转移至胆酸途径）以及降低的侧链氧化（线粒体26-羟基化）来解释。然而，胆酸生物合成中的侧链氧化可能是通过5 β-胆甾烷-3 α，7 α，12 α-三醇的微粒体25-羟基化而启动的，在对照组和无腱性黄瘤病肝脏中显著较低。因此，在胆酸和鹅去氧胆酸生物合成中，胆固醇侧链的裂解可能存在不同的机制。
To examine the defect in side-chain oxidation during the formation of bile acids in cerebrotendinous xanthomatosis, we measured in vitro hepatic microsomal hydroxylations at C-12 and C-25 and mitochondrial hydroxylation at C-26 and related them to the pool size and synthesis rates of cholic acid and chenodeoxycholic acid as determined by the isotope dilution technique. Hepatic microsomes and mitochondria were prepared from seven subjects with cerebrotendinous xanthomatosis and five controls. Primary bile acid synthesis was markedly reduced in cerebrotendinous xanthomatosis as follows: cholic acid, 133 +/- 30 vs. 260 +/- 60 mg/d in controls; and chenodeoxycholic acid, 22 +/- 10 vs. 150 +/- 30 mg/d in controls. As postulated for chenodeoxycholic acid synthesis, mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha-diol was present in all specimens and was 30-fold more active than the corresponding microsomal 25-hydroxylation. However, mean mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha-diol was less active in cerebrotendinous xanthomatosis than in controls: 59 +/- 17 compared with 126 +/- 21 pmol/mg protein per min. As for cholic acid synthesis, microsomal 25-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was substantially higher in cerebrotendinous xanthomatosis and control preparations (620 +/- 103 and 515 +/- 64 pmol/mg protein per min, respectively) than the corresponding control mitochondrial 26-hydroxylation of the same substrate (165 +/- 25 pmol/mg protein per min). Moreover in cerebrotendinous xanthomatosis, mitochondrial 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol-26-hydroxylase activity was one-seventh as great as in controls. Hepatic microsomal 12 alpha-hydroxylation, which may be rate-controlling for the cholic acid pathway, was three times more active in cerebrotendinous xanthomatosis than in controls: 1,600 vs. 500 pmol/mg protein per min. These results demonstrate severely depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation and pool size disproportionately greater than that for cholic acid. The deficiency of chenodeoxycholic acid can be accounted for by hyperactive microsomal 12 alpha-hydroxylation that diverts precursors into the cholic acid pathway combined with decreased side-chain oxidation (mitochondrial 26-hydroxylation). However, side-chain oxidation in cholic acid biosynthesis may be initiated via microsomal 25-hydroxylation of 5beta-cholestane-3alpha,7alpha,12alpha-triol was substantially lower in control and cerebrotendinous xanthomatosis liver. Thus, separate mechanisms may exist for the cleavage of the cholesterol side chain in cholic acid and chenodeoxycholic acid biosynthesis.