Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis
Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis
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DOI：
10.1210/me.2003-0179
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发表时间：
2004-03-01
影响因子：
--
通讯作者：
Azhar, S
中科院分区：
文献类型：
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作者：
Kraemer, FB;Shen, WJ;Azhar, S
类固醇激素是以胆固醇为前体合成的，其中很大一部分是由脂蛋白衍生的胆固醇酯选择性吸收提供的。肾上腺表达高水平的中性胆固醇酯水解酶活性，最近发现激素敏感脂肪酶(HSL)是肾上腺中性胆固醇酯水解酶活性的主要来源。为了确定HSL在肾上腺类固醇合成中的功能重要性，从对照组和HSL-/-小鼠分离肾上腺细胞，并在体外定量皮质酮的产生。结果表明，尽管雄性和雌性HSL-/-小鼠的肾上腺胆固醇酯含量都显著增加，但基础皮质酮的产生减少了大约50%。HSL-/-小鼠肾上腺细胞经二丁酰cAMP和脂蛋白诱导的最大皮质酮产量比对照组低约75-85%。在HSL-/-小鼠中，胆固醇转化为类固醇的过程中没有固有缺陷。在HSL-/-小鼠中，二丁酰cAMP刺激的高密度脂蛋白胆固醇酯到皮质酮的转化减少了97%。低密度脂蛋白受体表达的增加似乎是HSL-/-小鼠胆固醇输送的代偿机制之一。这些发现表明，HSL在功能上与选择性途径有关，并且在肾上腺类固醇合成的细胞内加工和胆固醇的可获得性中起关键作用。
Steroid hormones are synthesized using cholesterol as precursor, with a substantial portion supplied by the selective uptake of lipoprotein-derived cholesteryl esters. Adrenals express a high level of neutral cholesteryl ester hydrolase activity, and recently hormone-sensitive lipase (HSL) was shown to be responsible for most adrenal neutral cholesteryl ester hydrolase activity. To determine the functional importance of HSL in adrenal steroidogenesis, adrenal cells were isolated from control and HSL-/- mice, and the in vitro production of corticosterone was quantified. Results show that, even though adrenal cholesteryl ester content was substantially elevated in both male and female HSL-/- mice, basal corticosterone production was reduced approximately 50%. The maximum corticosterone production induced by dibutyryl cAMP, and lipoproteins was approximately 75-85% lower in adrenal cells from HSL-/- mice compared with control. There is no intrinsic defect in the conversion of cholesterol into steroids in HSL-/- mice. Dibutyryl cAMP-stimulated conversion of high-density lipoprotein cholesteryl esters into corticosterone was reduced 97% in HSL-/- mice. An increase in low-density lipoprotein receptor expression appears to be one of the compensatory mechanisms for cholesterol delivery in HSL-/- mice. These findings suggest that HSL is functionally linked to the selective pathway and is critically involved in the intracellular processing and availability of cholesterol for adrenal steroidogenesis.