Grav Hans J, Tronstad Karl J, Gudbrandsen Oddrun A, Berge Kjetil, Fladmark Kari E, Martinsen Tom C, Waldum Helge, Wergedahl Hege, Berge Rolf K
Institute for Nutrition Research, University of Oslo, N-0316 Oslo, Norway.
J Biol Chem. 2003 Aug 15;278(33):30525-33. doi: 10.1074/jbc.M303382200. Epub 2003 May 19.
Lowering of plasma triglyceride levels by hypolipidemic agents is caused by a shift in the liver cellular metabolism, which become poised toward peroxisome proliferator-activated receptor (PPAR) alpha-regulated fatty acid catabolism in mitochondria. After dietary treatment of rats with the hypolipidemic, modified fatty acid, tetradecylthioacetic acid (TTA), the energy state parameters of the liver were altered at the tissue, cell, and mitochondrial levels. Thus, the hepatic phosphate potential, energy charge, and respiratory control coefficients were lowered, whereas rates of oxygen uptake, oxidation of pyridine nucleotide redox pairs, beta-oxidation, and ketogenesis were elevated. Moderate uncoupling of mitochondria from TTA-treated rats was confirmed, as the proton electrochemical potential (Delta(p)) was 15% lower than controls. The change affected the Delta(Psi) component only, leaving the (Delta)pH component unaltered, suggesting that TTA causes induction of electrogenic ion transport rather than electrophoretic fatty acid activity. TTA treatment induced expression of hepatic uncoupling protein 2 (UCP-2) in rats as well as in wild type and PPARalpha-deficient mice, accompanied by a decreased double bond index of the mitochondrial membrane lipids. However, changes of mitochondrial fatty acid composition did not seem to be related to the effects on mitochondrial energy conductance. As TTA activates PPARdelta, we discuss how this subtype might compensate for deficiency of PPARalpha. The overall changes recorded were moderate, making it likely that liver metabolism can maintain its function within the confines of its physiological regulatory framework where challenged by a hypolipemic agent such as TTA, as well as others.
降血脂药物降低血浆甘油三酯水平是由肝细胞代谢的转变引起的，这种转变使肝脏倾向于过氧化物酶体增殖物激活受体（PPAR）α调节的线粒体脂肪酸分解代谢。在用降血脂的修饰脂肪酸十四烷基硫代乙酸（TTA）对大鼠进行饮食治疗后，肝脏的能量状态参数在组织、细胞和线粒体水平上发生了改变。因此，肝脏的磷酸势、能荷和呼吸控制系数降低，而氧摄取率、吡啶核苷酸氧化还原对的氧化、β氧化和生酮作用增强。经TTA处理的大鼠线粒体存在中度解偶联，因为质子电化学势（Δp）比对照组低15%。这种变化仅影响ΔΨ成分，而ΔpH成分未改变，这表明TTA导致了电生离子转运的诱导，而非电泳脂肪酸活性。TTA处理诱导大鼠以及野生型和PPARα缺陷型小鼠肝脏解偶联蛋白2（UCP-2）的表达，同时线粒体膜脂质的双键指数降低。然而，线粒体脂肪酸组成的变化似乎与对线粒体能量传导的影响无关。由于TTA激活PPARδ，我们讨论了该亚型如何补偿PPARα的缺陷。记录到的总体变化是适度的，这使得肝脏代谢在受到TTA等降血脂药物以及其他药物挑战时，有可能在其生理调节框架范围内维持其功能。
