Holness Mark J, Bulmer Karen, Smith Nicholas D, Sugden Mary C
Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK.
Biochem J. 2003 Feb 1;369(Pt 3):687-95. doi: 10.1042/BJ20021509.
Liver contains two pyruvate dehydrogenase kinases (PDKs), namely PDK2 and PDK4, which regulate glucose oxidation through inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Starvation increases hepatic PDK2 and PDK4 protein expression, the latter occurring, in part, via a mechanism involving peroxisome proliferator-activated receptor-alpha (PPARalpha). High-fat feeding and hyperthyroidism, which increase circulating lipid supply, enhance hepatic PDK2 protein expression, but these increases are insufficient to account for observed increases in hepatic PDK activity. Enhanced expression of PDK4, but not PDK2, occurs in part via a mechanism involving PPAR-alpha. Heterodimerization partners for retinoid X receptors (RXRs) include PPARalpha and thyroid-hormone receptors (TRs). We therefore investigated the responses of hepatic PDK protein expression to high-fat feeding and hyperthyroidism in relation to hepatic lipid delivery and disposal. High-fat feeding increased hepatic PDK2, but not PDK4, protein expression whereas hyperthyroidism increased both hepatic PDK2 and PDK4 protein expression. Both manipulations decreased the sensitivity of hepatic carnitine palmitoyltransferase I (CPT I) to suppression by malonyl-CoA, but only hyperthyrodism elevated plasma fatty acid and ketone-body concentrations and CPT I maximal activity. Administration of the selective PPAR-alpha activator WY14,643 significantly increased PDK4 protein to a similar extent in both control and high-fat-fed rats, but WY14,643 treatment and hyperthyroidism did not have additive effects on hepatic PDK4 protein expression. PPARalpha activation did not influence hepatic PDK2 protein expression in euthyroid rats, suggesting that up-regulation of PDK2 by hyperthyroidism does not involve PPARalpha, but attenuated the effect of hyperthyroidism to increase hepatic PDK2 expression. The results indicate that hepatic PDK4 up-regulation can be achieved by heterodimerization of either PPARalpha or TR with the RXR receptor and that effects of PPARalpha activation on hepatic PDK2 and PDK4 expression favour a switch towards preferential expression of PDK4.
肝脏含有两种丙酮酸脱氢酶激酶（PDKs），即PDK2和PDK4，它们通过对丙酮酸脱氢酶复合体（PDC）进行抑制性磷酸化来调节葡萄糖氧化。饥饿会增加肝脏中PDK2和PDK4的蛋白表达，后者部分是通过一种涉及过氧化物酶体增殖物激活受体α（PPARα）的机制实现的。高脂喂养和甲状腺功能亢进会增加循环脂质供应，增强肝脏中PDK2的蛋白表达，但这些增加不足以解释观察到的肝脏PDK活性的增加。PDK4而非PDK2的表达增强部分是通过一种涉及PPAR-α的机制实现的。视黄酸X受体（RXRs）的异二聚体伴侣包括PPARα和甲状腺激素受体（TRs）。因此，我们研究了肝脏PDK蛋白表达对高脂喂养和甲状腺功能亢进的反应，以及与肝脏脂质输送和处理的关系。高脂喂养增加了肝脏中PDK2而非PDK4的蛋白表达，而甲状腺功能亢进则增加了肝脏中PDK2和PDK4的蛋白表达。两种处理均降低了肝脏肉碱棕榈酰转移酶I（CPT I）对丙二酰辅酶A抑制的敏感性，但只有甲状腺功能亢进提高了血浆脂肪酸和酮体浓度以及CPT I的最大活性。给予选择性PPAR-α激活剂WY14,643在对照大鼠和高脂喂养大鼠中均显著增加了PDK4蛋白表达至相似程度，但WY14,643处理和甲状腺功能亢进对肝脏PDK4蛋白表达没有相加作用。PPARα激活对甲状腺功能正常大鼠的肝脏PDK2蛋白表达没有影响，这表明甲状腺功能亢进对PDK2的上调不涉及PPARα，但减弱了甲状腺功能亢进增加肝脏PDK2表达的作用。结果表明，通过PPARα或TR与RXR受体的异二聚化可实现肝脏PDK4的上调，并且PPARα激活对肝脏PDK2和PDK4表达的影响有利于向PDK4的优先表达转变。
