Identification and Mechanism of 10-Carbon Fatty Acid as Modulating Ligand of Peroxisome Proliferator-activated Receptors
Identification and Mechanism of 10-Carbon Fatty Acid as Modulating Ligand of Peroxisome Proliferator-activated Receptors
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DOI：
10.1074/jbc.m111.294785
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发表时间：
2012-01-02
影响因子：
4.8
通讯作者：
Xu, H. Eric
中科院分区：
文献类型：
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作者：
Malapaka, Raghu R. V.;Khoo, SokKean;Xu, H. Eric
过氧化物酶体增殖体激活受体（PPAR α， - β / δ和- γ）是核受体的一个亚家族，在葡萄糖和脂质代谢中起关键作用。PPAR γ是噻唑烷二酮类降糖药的分子靶点，具有许多副作用。PPAR γ也被长链不饱和脂肪酸或氧化/硝化脂肪酸激活，但其与中链脂肪酸的关系尚不清楚，尽管中链甘油三酯油已被用于控制体重增加和血糖指数。在这里，我们证明了癸酸（DA），一种10碳脂肪酸和中链甘油三酯油的主要成分，是PPAR γ的直接配体。DA结合并部分激活PPAR γ而不导致脂肪形成。晶体结构显示DA占据了一个新的结合位点，仅部分稳定AF-2螺旋。DA也与PPAR α和PPAR β / δ结合较弱。用DA及其甘油三酯形式治疗可以改善糖尿病小鼠的葡萄糖敏感性和脂质谱，而不会增加体重。总之，这些结果表明DA是PPAR的调节配体，其结构可以帮助设计更好、更安全的PPAR γ基药物。
Peroxisome proliferator-activated receptors (PPAR alpha, -beta/delta, and -gamma) are a subfamily of nuclear receptors that plays key roles in glucose and lipid metabolism. PPAR gamma is the molecular target of the thiazolidinedione class of antidiabetic drugs that has many side effects. PPAR gamma is also activated by long chain unsaturated or oxidized/nitrated fatty acids, but its relationship with the medium chain fatty acids remains unclear even though the medium chain triglyceride oils have been used to control weight gain and glycemic index. Here, we show that decanoic acid (DA), a 10-carbon fatty acid and a major component of medium chain triglyceride oils, is a direct ligand of PPAR gamma. DA binds and partially activates PPAR gamma without leading to adipogenesis. Crystal structure reveals that DA occupies a novel binding site and only partially stabilizes the AF-2 helix. DA also binds weakly to PPAR alpha and PPAR beta/delta. Treatments with DA and its triglyceride form improve glucose sensitivity and lipid profiles without weight gain in diabetic mice. Together, these results suggest that DA is a modulating ligand for PPARs, and the structure can aid in designing better and safer PPAR gamma-based drugs.