Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes.
Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes.
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DOI：
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发表时间：
1999-11
影响因子：
6.5
通讯作者：
F. Lammert;D. Q. Wang;B. Paigen;M. Carey
中科院分区：
文献类型：
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作者：
F. Lammert;D. Q. Wang;B. Paigen;M. Carey
肝脂质调节酶在胆固醇结石中起主要作用还是次要作用，目前尚无共识。我们使用带有Lith基因的近交系小鼠来评估这个问题，Lith基因决定胆固醇结石的易感性。我们研究了在C57 L/J和SWR/J以及重组近交系（AKXL-29）小鼠中胆固醇生物合成（HMG-CoA还原酶）、胆固醇酯化（酰基-CoA：胆固醇酰基转移酶）以及胆盐合成的“中性”（胆固醇7 α-羟化酶）和“酸性”（甾醇27-羟化酶）途径中的调节酶的活性，所有这些小鼠都具有易感的Lith等位基因，并将它们与具有抗性Lith等位基因的AKR/J小鼠进行比较。我们测定了肝酶活性的雄性小鼠之前，并在频繁的时间间隔喂养致石饮食（15%的乳脂，1%的胆固醇，0.5%的胆酸）12周。基础活动的食物显示显着的遗传变异HMG-CoA还原酶，甾醇27-羟化酶，酰基辅酶A：胆固醇酰基转移酶，但不为胆固醇7 α-羟化酶。作为对致石饮食的响应，两种胆盐合成途径中的调节酶的活性协同下调，并且与胆固醇结晶和胆结石的患病率呈负相关。与胆结石抗性小鼠相比，显著较高的HMG-CoA还原酶活性以及较低的两种胆盐合成酶活性是具有易感Lith等位基因的小鼠的酶表型的标志。对多种酶变化的最简单的解释是，原发性Lith表型诱导继发性事件，以增加胆固醇的可用性，从而向肝细胞小管膜提供甾醇，从而分泌过多进入胆汁。
There is no consensus whether hepatic lipid regulatory enzymes play primary or secondary roles in cholesterol cholelithiasis. We have used inbred mice with Lith genes that determine cholesterol gallstone susceptibility to evaluate the question. We studied activities of regulatory enzymes in cholesterol biosynthesis (HMG-CoA reductase), cholesterol esterification (acyl-CoA:cholesterol acyltransferase) and the "neutral" (cholesterol 7alpha-hydroxylase) and "acidic" (sterol 27-hydroxylase) pathways of bile salt synthesis in strains C57L/J and SWR/J as well as recombinant inbred (AKXL-29) mice, all of which have susceptible Lith alleles, and compared them to AKR/J mice with resistant Lith alleles. We determined hepatic enzyme activities of male mice before and at frequent intervals during feeding a lithogenic diet (15% dairy fat, 1% cholesterol, 0.5% cholic acid) for 12 weeks. Basal activities on chow show significant genetic variations for HMG-CoA reductase, sterol 27-hydroxylase, and acyl-CoA: cholesterol acyltranferase, but not for cholesterol 7alpha-hydroxylase. In response to the lithogenic diet, activities of the regulatory enzymes in the two bile salt synthetic pathways are coordinately down-regulated and correlate inversely with prevalence rates of cholesterol crystals and gallstones. Compared with gallstone-resistant mice, significantly higher HMG-CoA reductase activities together with lower activities of both bile salt synthetic enzymes are hallmarks of the enzymatic phenotype in mice with susceptible Lith alleles. The most parsimonious explanation for the multiple enzymatic alterations is that the primary Lith phenotype induces secondary events to increase availability of cholesterol to supply the sterol to the hepatocyte canalicular membrane for hypersecretion into bile.