Koch Alexander, König Bettina, Stangl Gabriele I, Eder Klaus
Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, D-06108 Halle Saale, Germany.
Exp Biol Med (Maywood). 2008 Mar;233(3):356-65. doi: 10.3181/0706-RM-168.
We tested the hypothesis that transcription of novel organic cation transporters (OCTNs) is directly regulated by peroxisome proliferator-activated receptor (PPAR)-alpha. Therefore, wild-type mice and mice deficient in PPAR alpha (PPAR alpha-/-) were treated with the PPAR alpha agonist WY 14,643. Wild-type mice treated with WY 14,643 had a greater abundance of OCTN2 mRNA in their liver, muscle, kidney, and small intestine and a greater abundance of OCTN3 mRNA in kidney and small intestine than did untreated wild-type mice (P < 0.05). Moreover, wild-type mice treated with WY 14,643 had greater mRNA abundances of enzymes involved in hepatic carnitine synthesis (4-N-trimethylaminobutyraldehyde dehydrogenase, gamma-butyrobetaine dioxygenase) and increased carnitine concentrations in liver and muscle than did untreated wild-type mice (P < 0.05). Untreated PPAR alpha-/- mice had a lower abundance of OCTN2 mRNA in liver, kidney, and small intestine and lower carnitine concentrations in plasma, liver, and kidney than did untreated wild-type mice (P < 0.05). In PPAR alpha-/- mice, treatment with WY 14,643 did not influence mRNA abundance of OCTN2 and OCTN3 and carnitine concentrations in all tissues analyzed. The abundance of OCTN1 mRNA in all the tissues analyzed was not changed by treatment with WY 14,643 in wild-type or PPAR alpha-/- mice. In conclusion, this study shows that transcriptional upregulation of OCTN2 and OCTN3 in tissues and of enzymes involved in hepatic carnitine biosynthesis are mediated by PPAR alpha. It also shows that PPAR alpha mediates changes of whole-body carnitine homeostasis in mice by upregulation of carnitine transporters and enzymes involved in carnitine synthesis.
新型有机阳离子转运体（OCTN）的转录受过氧化物酶体增殖物激活受体（PPAR）-α直接调控。因此，用PPAR-α激动剂WY 14,643处理野生型小鼠和PPAR-α基因敲除小鼠（PPARα-/-）。与未处理的野生型小鼠相比，用WY 14,643处理的野生型小鼠肝脏、肌肉、肾脏和小肠中OCTN2 mRNA丰度更高，肾脏和小肠中OCTN3 mRNA丰度更高（P<0.05）。此外，与未处理的野生型小鼠相比，用WY 14,643处理的野生型小鼠肝脏中参与肉碱合成的酶（4-N-三甲基氨基丁醛脱氢酶、γ-丁酰甜菜碱双加氧酶）的mRNA丰度更高，肝脏和肌肉中的肉碱浓度增加（P<0.05）。与未处理的野生型小鼠相比，未处理的PPARα-/-小鼠肝脏、肾脏和小肠中OCTN2 mRNA丰度较低，血浆、肝脏和肾脏中的肉碱浓度较低（P<0.05）。在PPARα-/-小鼠中，用WY 14,643处理对所有分析组织中OCTN2和OCTN3的mRNA丰度以及肉碱浓度均无影响。在野生型或PPARα-/-小鼠中，用WY 14,643处理对所有分析组织中OCTN1 mRNA的丰度均无影响。总之，本研究表明，组织中OCTN2和OCTN3以及肝脏肉碱生物合成相关酶的转录上调是由PPAR-α介导的。研究还表明，PPAR-α通过上调肉碱转运体和参与肉碱合成的酶来介导小鼠全身肉碱稳态的变化。
