A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-α.: (PPAR-α) and PPAR-γ -: Effect of PPAR-α activation on abnormal lipid metabolism in liver of Zucker fatty rats
A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-α.: (PPAR-α) and PPAR-γ -: Effect of PPAR-α activation on abnormal lipid metabolism in liver of Zucker fatty rats
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DOI：
10.2337/diabetes.47.12.1841
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发表时间：
1998-12-01
期刊：
影响因子：
7.7
通讯作者：
Kadowaki, T
中科院分区：
文献类型：
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作者：
Murakami, K;Tobe, K;Kadowaki, T
我们研究了一种新型的噻唑烷二酮(TZD)衍生物KRP-297的生物活性及其分子基础。当给予肥胖的Zucker肥胖大鼠(肥胖大鼠)两周时，Krp-297与ERL-49,653不同，恢复了肝脏中减少的脂质氧化，即由[C-14]棕榈酸产生的二氧化碳和酮体，分别减少了39%(P<；0.05)和57%(P<；0.01)。KRP-297在抑制肝脏脂肪生成和甘油三酯蓄积方面也明显优于BRL-49,653。为了了解KRP-297生物学作用的分子基础，我们研究了KRP-297对可能在脂质代谢中起关键作用的过氧化体增殖物激活受体(PPAR)亚型的影响。与经典的TZD衍生物不同，KRP-297同时激活PPAR-α和PPAR-γ，其有效浓度的中位数分别为1.0和0.8mU·mol/L。此外，放射性标记的[H-3]Krp-297与PPAR-α和PPAR-γ直接结合，解离常数分别为228和326nmol/L。与此同时，Krp-297，而不是BRL-49,653，增加了肝脏中酰基辅酶A氧化酶的mRNA和活性(分别是1.5倍[P<；0.01]和1.8倍[P<；0.05])，据报道，这种氧化酶受PPAR-α的调节。与BRL-49,653(P<；0.01)相比，KRP-297(P<；0.05)在诱导PPAR-γ调节的脂肪组织中aP2基因的表达方面不如BRL-49,653(P<；0.01)。提示PPAR-α激动剂对肥胖大鼠肝脏脂代谢异常具有保护作用。
We investigated the biological activity of a novel thiazolidinedione (TZD) derivative, KRP-297, and the molecular basis of this activity. When administered to obese Zucker fatty rats (obese rats) at 10 mg/kg for 2 weeks, KRP-297, unlike ERL-49,653, restored reduced lipid oxidation, that is, CO2 and ketone body production from [C-14]palmitic acid, in the liver by 39% (P < 0.05) and 57% (P < 0.01), respectively. KRP-297 was also significantly more effective than BRL-49,653 in the inhibition of enhanced lipogenesis and triglyceride accumulation in the liver. To understand the molecular basis of the biological effects of KRP-297, we examined the effect on peroxisome proliferator-activated receptor (PPAR) isoforms, which may play key roles in lipid metabolism. Unlike classical TZD derivatives, KRP-297 activated both PPAR-alpha, and PPAR-gamma, with median effective concentrations of 1.0 and 0.8 mu mol/l, respectively. Moreover, radiolabeled [H-3]KRP-297 bound directly to PPAR-alpha and PPAR-gamma with dissociation constants of 228 and 326 nmol/l, respectively. Concomitantly, KRP-297, but not BRL-49,653, increased the mRNA and the activity (1.5-fold [P < 0.01] and 1.8-fold [P < 0.05], respectively) of acyl-CoA oxidase, which has been reported to be regulated by PPAR-alpha, in the liver. By contrast, KRP-297 (P < 0.05) was less potent than BRL-49,653 (P < 0.01) in inducing the PPAR-gamma-regulated aP2 gene mRNA expression in the adipose tissues. These results suggest that PPAR-alpha agonism has a protective effect against abnormal lipid metabolism in liver of obese rats.