In vivo and in vitro regulation of sterol 27-hydroxylase in the liver during the acute phase response -: Potential role of hepatocyte nuclear factor-1
In vivo and in vitro regulation of sterol 27-hydroxylase in the liver during the acute phase response -: Potential role of hepatocyte nuclear factor-1
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DOI：
10.1074/jbc.m102516200
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发表时间：
2001-08-10
影响因子：
4.8
通讯作者：
Feingold, KR
中科院分区：
文献类型：
--
作者：
Memon, RA;Moser, AH;Feingold, KR
宿主对感染的反应与促进脂蛋白产生的脂质代谢的几种改变有关。这些变化可以通过脂多糖（LPS）的管理再现。LPS刺激肝胆固醇合成并抑制胆固醇向胆汁酸的转化。LPS下调肝脏胆固醇7 α-羟化酶，胆汁酸合成经典途径中的限速酶。我们现在证明，LPS显着降低固醇27-羟化酶，在胆汁酸合成的替代途径的限速酶，在叙利亚仓鼠的肝脏中的活性。此外，LPS逐渐降低肝固醇27-羟化酶mRNA水平的75%，与对照组相比，在24小时的治疗期。LPS还降低小鼠肝脏中的氧固醇7 α-羟化酶mRNA水平。在HepG 2细胞中的体外研究表明，肿瘤坏死因子和白细胞介素（IL）-1降低甾醇27-羟化酶mRNA水平分别为48%和80%，而IL-6没有这样的效果。IL-1诱导的甾醇27-羟化酶mRNA表达的降低发生较早，持续48小时，并且需要非常低的剂量。体内IL-1治疗也降低了叙利亚仓鼠的肝固醇27-羟化酶mRNA水平。研究LPS诱导的甾醇27-羟化酶降低的分子机制的研究表明，LPS显著降低肝细胞核因子-1的mRNA和蛋白水平，肝细胞核因子-1是调节肝脏中甾醇27-羟化酶的转录因子。此外，LPS降低了70%的仓鼠肝细胞核提取物中的HNF-1的结合活性，这表明LPS可能通过降低HNF-1与其启动子的结合来下调甾醇27-羟化酶。结合我们早期对胆固醇7 α-羟化酶的研究，这些数据表明LPS抑制胆汁酸合成的经典途径和替代途径。肝脏中胆汁酸合成的减少将减少胆固醇催化剂，从而有助于由LPS和细胞因子诱导的肝脂蛋白产生的增加。
The host response to infection is associated with several alterations in lipid metabolism that promote lipoprotein production. These changes can be reproduced by lipopolysaccharide (LPS) administration. LPS stimulates hepatic cholesterol synthesis and suppresses the conversion of cholesterol to bile acids. LPS down-regulates hepatic cholesterol 7 alpha -hydroxylase, the rate-limiting enzyme in the classic pathway of bile acid synthesis. We now demonstrate that LPS markedly decreases the activity of sterol 27-hydroxylase, the rate-limiting enzyme in the alternate pathway of bile acid synthesis, in the liver of Syrian hamsters. Moreover, LPS progressively decreases hepatic sterol 27-hydroxylase mRNA levels by 75% compared with controls over a 24-h treatment period. LPS also decreases oxysterol 7 alpha -hydroxylase mRNA levels in mouse liver. In vitro studies in HepG2 cells demonstrate that tumor necrosis factor and interleukin (IL)-1 decrease sterol 27-hydroxylase MRNA levels by 48 and 80%, respectively, whereas IL-6 has no such effect. The IL-1-induced decrease in sterol 27-hydroxylase mRNA expression occurs early, is sustained for 48 h, and requires very low doses. In vivo IL-1 treatment also lowers hepatic sterol 27-hydroxylase mRNA levels in Syrian hamsters. Studies investigating the molecular mechanisms of LPS-induced decrease in sterol 27-hydroxylase show that LPS markedly decreases mRNA and protein levels of hepatocyte nuclear factor-1 a transcription factor that regulates sterol 27-hydroxylase, in the liver. Moreover, LPS decreases the binding activity of HNF-1 by 70% in nuclear extracts in hamster liver, suggesting that LPS may down-regulate sterol 27-hydroxylase by decreasing the binding of HNF-1 to its promoter. Coupled with our earlier studies on cholesterol 7 alpha -hydroxylase, these data indicate that LPS suppresses both the classic and alternate pathways of bile acid synthesis. A decrease in bile acid synthesis mi liver would reduce cholesterol catabolism and thereby contribute to the increase in hepatic lipoprotein production that is induced by LPS and cytokines.