Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
Biomed Pharmacother. 2020 Jul;127:110155. doi: 10.1016/j.biopha.2020.110155. Epub 2020 May 12.
Dual-PPAR-α/γ agonist has the dual potentials to improve insulin resistance (IR) and hepatic steatosis associated with obesity. This study aimed to investigate whether dehydroabietic acid (DA), a naturally occurred compound, can bind to and activate both PPAR-γ and PPAR-α to ameliorate IR and hepatic steatosis in high-fat diet (HFD)-fed mice.. We found that DA formed stable hydrogen bonds with the ligand-binding domains of PPAR-γ and PPAR-α. DA treatment also promoted 3T3-L1 differentiation via PPAR-γ activation, and mitochondrial oxygen consumption in HL7702 cells via PPAR-α activation. In HFD-fed mice, DA treatment alleviated glucose intolerance and IR, and reduced hepatic steatosis, liver injury markers (ALT, AST), and lipid accumulation, and promoted mRNA expression of PPAR-γ and PPAR-α signaling elements involved in IR and lipid metabolism in vivo and in vitro, and inhibited mRNA expression of pro-inflammatory factors. Therefore, DA is a dual-PPAR-α/γ and PPAR-γ partial agonist, which can attenuate IR and hepatic steatosis induced by HFD-consumption in mice.
双重过氧化物酶体增殖物激活受体-α/γ 激动剂具有改善与肥胖相关的胰岛素抵抗（IR）和肝脂肪变性的双重潜力。本研究旨在探讨一种天然存在的化合物——去氢枞酸（DA）是否可以与 PPAR-γ 和 PPAR-α 结合并激活它们，从而改善高脂肪饮食（HFD）喂养小鼠的 IR 和肝脂肪变性。我们发现，DA 与 PPAR-γ 和 PPAR-α 的配体结合域形成稳定的氢键。DA 处理还通过激活 PPAR-γ 促进 3T3-L1 分化，通过激活 PPAR-α 促进 HL7702 细胞的线粒体耗氧量。在 HFD 喂养的小鼠中，DA 处理可缓解葡萄糖不耐受和 IR，并减少肝脂肪变性、肝损伤标志物（ALT、AST）和脂质积累，促进体内和体外涉及 IR 和脂质代谢的 PPAR-γ 和 PPAR-α 信号通路基因的表达，并抑制促炎因子的基因表达。因此，DA 是一种双重过氧化物酶体增殖物激活受体-α/γ 和 PPAR-γ 部分激动剂，可减轻 HFD 喂养小鼠的 IR 和肝脂肪变性。
