Schoonjans K, Staels B, Grimaldi P, Auwerx J
Laboratoire de Biologie des Régulations chez les Eucaryotes, Université de Nice-Sophia Antipolis, France.
Eur J Biochem. 1993 Sep 1;216(2):615-22. doi: 10.1111/j.1432-1033.1993.tb18181.x.
Several enzymes of the beta-oxidation pathway have been shown to be induced after stimulation with peroxisomal proliferators, including several hypolipidemic drugs. We investigated the regulation of the long-chain-acyl-CoA synthetase (ACS) gene in the liver. Fenofibrate, a hypolipidemic drug and potent peroxisomal proliferator, induced ACS gene expression in several tissues. In liver, large increases in ACS mRNA levels and ACS activity were observed after fenofibrate administration. Adipose tissue ACS mRNA levels and ACS activity were also stimulated upon fibrate treatment but to a lesser extent in comparison with liver ACS mRNA. Kidney ACS mRNA was only weakly induced, except for the highest dose and the longest treatment period, where a strong induction was observed. In contrast to these tissues, heart ACS mRNA and ACS activity remained almost unchanged after fenofibrate treatment. These effects of fenofibrate could be reproduced by other fibrates such as clofibrate. In addition, it is demonstrated that both nutritional composition and liver proliferation trigger ACS gene expression in liver. Consequently, these data suggest that ACS is a highly regulated enzyme with a potentially important control function in lipid metabolism.
β-氧化途径的几种酶已被证明在受到过氧化物酶体增殖剂刺激后会被诱导，其中包括几种降血脂药物。我们研究了肝脏中长链酰基辅酶A合成酶（ACS）基因的调控。非诺贝特是一种降血脂药物，也是一种强效的过氧化物酶体增殖剂，它能在多种组织中诱导ACS基因表达。在肝脏中，给予非诺贝特后观察到ACS mRNA水平和ACS活性大幅增加。贝特类药物治疗后，脂肪组织的ACS mRNA水平和ACS活性也受到刺激，但与肝脏ACS mRNA相比程度较小。肾脏ACS mRNA仅受到微弱诱导，除了最高剂量和最长治疗期，此时观察到强烈诱导。与这些组织不同，非诺贝特治疗后心脏ACS mRNA和ACS活性几乎保持不变。非诺贝特的这些作用可以被其他贝特类药物如氯贝丁酯重现。此外，研究表明营养成分和肝脏增殖都会触发肝脏中ACS基因的表达。因此，这些数据表明ACS是一种高度受调控的酶，在脂质代谢中具有潜在的重要控制功能。
