Coadministration of a liver X receptor agonist and a peroxisome proliferator activator receptor-α agonist in mice:: Effects of nuclear receptor interplay on high-density lipoprotein and triglyceride metabolism in vivo
Coadministration of a liver X receptor agonist and a peroxisome proliferator activator receptor-α agonist in mice:: Effects of nuclear receptor interplay on high-density lipoprotein and triglyceride metabolism in vivo
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DOI：
10.1124/jpet.103.064535
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发表时间：
2004-06-01
影响因子：
3.5
通讯作者：
Cao, GQ
中科院分区：
文献类型：
--
作者：
Beyer, TP;Schmidt, RJ;Cao, GQ
肝脏 X 受体 (LXR) 是调节胆固醇和脂肪酸代谢的主要转录因子。用特定的合成 LXR 激动剂 N-(2,2,2-三氟乙基)-N-[4-[2,2,2-三氟-1-羟基-1(三氟甲基)乙基]苯基]-苯磺酰胺 (T0901317) 治疗 C57B6 小鼠，导致高密度脂蛋白升高 (HDL) 胆固醇以及血浆和肝脏甘油三酯。已知过氧化物酶体增殖物激活受体-α (PPARα) 激动剂可诱导过氧化物酶体脂肪酸 β-氧化，并介导 HDL 胆固醇代谢。我们探索了这样的假设：同时激活 PPARα 和 LXR 可能会对 HDL 胆固醇升高产生累加效应，并减弱甘油三酯的积累。 T0901317 和特定 PPARα 激动剂 [4-氯-6-(2,3-xylidino)-2-嘧啶基硫代乙酸 (Wy14643)] 在小鼠中共同给药导致 HDL 胆固醇协同升高，这主要与富含 apoE 和 apoAl 的 HDL 颗粒增大有关。肝脏磷脂转移蛋白 (PLTP) mRNA 和血浆 PLTP 活性进一步升高，表明 PLTP 在观察到的 HDL 胆固醇升高中发挥作用。 LXR 激活引起的血浆甘油三酯水平的中度升高有所减少，而与 PPARα 激动剂共同给药后，肝脏中甘油三酯的积累没有改变。正如预期的那样，PPARα 激活后，肝脏中的过氧化物酶体脂肪酸 β 氧化显着升高。有趣的是，通过 T0901317 激活 LXR 也导致过氧化物酶体脂肪酸 β-氧化显着增加。甾醇调节元件结合蛋白 1c 的表达被 LXR 激动剂显着上调，但不会因 PPARα 激动剂治疗而改变。 LXR 激动剂和 PPARα 激动剂共同给药后，肝脏脂蛋白脂肪酶表达进一步增加。我们的研究标志着首次探索核受体对体内脂质稳态的相互作用。
Liver X receptors (LXRs) are master transcription factors regulating cholesterol and fatty acid metabolism. Treatment of C57B6 mice with a specific synthetic LXR agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317), resulted in elevated high-density lipoprotein (HDL) cholesterol as well as plasma and liver triglycerides. Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists are known to induce peroxisomal fatty acid beta-oxidation and also mediate HDL cholesterol metabolism. We have explored the hypothesis that simultaneous activation of PPARalpha and LXR may lead to additive effects on HDL cholesterol elevation as well as attenuation of triglyceride accumulation. Coadministration of T0901317 and the specific PPARalpha agonist [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy14643)] in mice led to synergistic elevation of HDL cholesterol that was primarily associated with enlarged HDL particles enriched with apoE and apoAl. Liver phospholipid transfer protein (PLTP) mRNA and plasma PLTP activity were additively elevated, suggesting a role of PLTP in the observed HDL cholesterol elevation. Moderate increases in plasma triglyceride levels induced by LXR activation was reduced, whereas the accumulation of triglyceride in the liver was not altered upon coadministration of the PPARalpha agonist. Peroxisomal fatty acid beta-oxidation in the liver was dramatically elevated upon PPARalpha activation as expected. Interestingly, activation of LXRs via T0901317 also led to a significant increase in peroxisomal fatty acid beta-oxidation. Sterol regulatory element binding protein 1c expression was dramatically up-regulated by the LXR agonist but was not changed with PPARalpha agonist treatment. Liver lipoprotein lipase expression was additively increased upon LXR agonist and PPARalpha agonist coadministration. Our studies mark the first exploration of nuclear receptor interplay on lipid homeostasis in vivo.