Effects of peroxisome proliferator-activated receptor α activation on pathways contributing to cholesterol homeostasis in rat hepatocytes
Effects of peroxisome proliferator-activated receptor α activation on pathways contributing to cholesterol homeostasis in rat hepatocytes
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DOI：
10.1016/j.bbalip.2004.04.004
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发表时间：
2004-07-05
影响因子：
4.8
通讯作者：
Bournot, P
中科院分区：
文献类型：
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作者：
Le Jossic-Corcos, C;Duclos, S;Bournot, P
贝特类药物激活过氧化物酶体增殖物激活受体α（PPARalpha）可控制参与肝胆固醇代谢的几种基因的表达。其他基因可以间接控制细胞胆固醇利用率的变化。为了进一步了解贝特类药物如何影响胆固醇合成，我们同时研究了肝脏中有助于胆固醇稳态的代谢途径的变化。环丙贝特增加大鼠肝细胞中HMG-CoA还原酶和FPP合成酶mRNA水平，以及[C-14]醋酸盐和[H-3]甲羟戊酸的胆固醇生成。在非诺贝特和WY-14，643处理的小鼠中观察到的上调在PPARalpha缺失小鼠中被消除，显示了PPARalpha的重要作用。在三种固醇调节元件结合蛋白（SREBP）mRNA种类中，只有SREBP-1c水平显著升高。在环丙贝特处理的肝细胞中，胆固醇流出。降低，与胆固醇酯储存和胆汁酸合成平行。正如预期的那样，AOX表达被强烈诱导，支持过氧化物酶体增殖的证据。综上所述，这些结果表明贝特类药物可导致肝细胞中胆固醇耗竭，可能部分原因是过氧化物酶体增殖对胆固醇的重要需求，并通过随后的补偿现象增加胆固醇生成。这种胆固醇生成调节可以在体内发生，在对PPARalpha配体的过氧化物酶体增殖作用有反应的物种中。(C)2004 Elsevier B. V.保留所有权利。
Peroxisome proliferator-activated receptor alpha (PPARalpha) activation by fibrates controls expression of several genes involved in hepatic cholesterol metabolism. Other genes could be indirectly controlled in response to changes in cellular cholesterol availability. To further understand how fibrates may affect cholesterol synthesis, we investigated in parallel the changes in the metabolic pathways contributing to cholesterol homeostasis in liver. Ciprofibrate increased HMG-CoA reductase and FPP synthase mRNA levels in rat hepatocytes, together with cholesterogenesis from [C-14] acetate and [H-3] mevalonate. The up-regulation observed in fenofibrate- and WY-14,643-treated mice was abolished in PPARalpha-null mice, showing an essential role of PPAR alpha. Among the three sterol regulatory element-binding protein (SREBP) mRNA species, only SREBP-1c level was significantly increased. In ciprofibrate-treated hepatocytes, cholesterol efflux. was decreased, in parallel with cholesteryl ester storage and bile acids synthesis. As expected, AOX expression was strongly induced, supporting evidence of the peroxisome proliferation. Taken together, these results show that fibrates can cause cholesterol depletion in hepatocytes, possibly in part as a consequence of an important requirement of cholesterol for peroxisome proliferation, and increase cholesterogenesis by a compensatory phenomenon afterwards. Such cholesterogenesis regulation could occur in vivo, in species responsive to the peroxisome proliferative effect of PPARalpha ligands. (C) 2004 Elsevier B.V. All rights reserved.