Liu Phillip C C, Huber Reid, Stow Mark D, Schlingmann Karen L, Collier Paul, Liao Boshan, Link John, Burn Tim C, Hollis Greg, Young Peter R, Mukherjee Ranjan
Department of Biotechnology, Experimental Station, Bristol-Myers Squibb Company, Wilmington, DE 19880, USA.
J Steroid Biochem Mol Biol. 2003 May;85(1):71-9. doi: 10.1016/s0960-0760(03)00135-3.
The peroxisome proliferator activated receptor alpha (PPARalpha) plays a key role in regulating fatty acid metabolism by regulating expression of genes involved in fatty acid oxidation. To identify endogenous transcripts that could be used as surrogate markers for on-target activity of PPARalpha agonists, we employed a global profiling approach using DNA microarrays. The HK-2 cell line derived from proximal tubules of the human kidney, showed induction of several genes, including pyruvate dehydrogenase kinase 4 (PDK-4) and adipocyte differentiation related protein (ADRP) by PPARalpha ligands. HK-2 cells express detectable levels of PPARalpha and its dimerization partner the retinoid X receptor (RXRalpha) proteins. Induction of PDK-4 in these cells correlates with induction of PDK-4 in the liver of fat-fed hamsters. The magnitude of fibrate induction of PDK-4 in the liver also mirrors the decrease in serum triglyceride levels. Thus, induction of PDK-4 by PPARalpha agonists in the HK-2 cell model closely correlates with its induction in vivo and may represent an early marker for PPARalpha agonist action.
过氧化物酶体增殖物激活受体α（PPARα）通过调节参与脂肪酸氧化的基因表达，在调节脂肪酸代谢中起关键作用。为了鉴定可用作PPARα激动剂靶向活性替代标志物的内源性转录本，我们采用了基于DNA微阵列的全局分析方法。源自人肾近端小管的HK-2细胞系显示，PPARα配体可诱导包括丙酮酸脱氢酶激酶4（PDK-4）和脂肪细胞分化相关蛋白（ADRP）在内的多种基因。HK-2细胞表达可检测水平的PPARα及其二聚化伴侣视黄酸X受体（RXRα）蛋白。这些细胞中PDK-4的诱导与高脂喂养仓鼠肝脏中PDK-4的诱导相关。贝特类药物对肝脏中PDK-4的诱导程度也反映了血清甘油三酯水平的降低。因此，在HK-2细胞模型中，PPARα激动剂对PDK-4的诱导与其在体内的诱导密切相关，可能代表PPARα激动剂作用的早期标志物。
