Silvestri Elena, de Lange Pieter, Moreno Maria, Lombardi Assunta, Ragni Maurizio, Feola Anna, Schiavo Luigi, Goglia Fernando, Lanni Antonia
Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italia.
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):486-95. doi: 10.1016/j.bbabio.2006.02.016. Epub 2006 Mar 23.
Fibrates (anti-hyperlipidemic agents) enhance the mRNA expression of uncoupling protein 2 (UCP2) in the liver and that of uncoupling protein 3 (UCP3) in skeletal muscle in standard-diet-fed rats and induce a de novo expression of UCP3 (mRNA and protein) in the liver of high-fat-fed rats. Here, we report that in the liver of normal rats, fenofibrate induces a de novo expression of UCP3 and a 6-fold increase in UCP2 mRNA, whereas UCP2 protein was not detectable. Indeed, we evidenced an ORF in UCP2 exon 2 potentially able to inhibit the expression of the protein. Fenofibrate increases the expression and activity of hepatic enzymes and cofactors involved in lipid handling and UCP3 activity and, as is the case for UCP3, induces other muscle-specific genes (e.g., Carnitine palmitoyl transferase 1b and Ubiquinone biosynthesis protein COQ7 homolog). In addition, we demonstrated that in mitochondria from fenofibrate-treated rats a palmitoyl-carnitine-induced GDP-sensitive uncoupling takes place, involving UCP3 rather than other uncouplers (i.e., UCP2 and Adenine Nucleotide Translocase). Thus, the liver of fenofibrate-treated standard-diet- fed rat is a useful model for investigations of the biochemical functions of UCP3 and allowed us to demonstrate that fenofibrate programs a gene-expression pattern able to modulate lipid handling and UCP3 activation.
在标准饮食喂养的大鼠中，贝特类药物（抗高脂血症药物）可增强肝脏中解偶联蛋白2（UCP2）的mRNA表达以及骨骼肌中解偶联蛋白3（UCP3）的mRNA表达，并在高脂饮食喂养的大鼠肝脏中诱导UCP3（mRNA和蛋白）的从头表达。在此，我们报告在正常大鼠肝脏中，非诺贝特可诱导UCP3的从头表达以及UCP2 mRNA增加6倍，而未检测到UCP2蛋白。实际上，我们证实UCP2外显子2中存在一个开放阅读框，可能能够抑制该蛋白的表达。非诺贝特可增加参与脂质处理的肝酶和辅助因子的表达及活性以及UCP3的活性，并且与UCP3的情况一样，可诱导其他肌肉特异性基因（如肉碱棕榈酰转移酶1b和泛醌生物合成蛋白COQ7同源物）的表达。此外，我们证明在非诺贝特处理的大鼠的线粒体中，发生了棕榈酰肉碱诱导的对GDP敏感的解偶联，涉及UCP3而非其他解偶联剂（即UCP2和腺嘌呤核苷酸转位酶）。因此，非诺贝特处理的标准饮食喂养大鼠的肝脏是研究UCP3生化功能的有用模型，并使我们能够证明非诺贝特可编排一种能够调节脂质处理和UCP3激活的基因表达模式。
