University of Ioannina, Faculty of Medicine, Department of Pharmacology, Ioannina GR-45110, Greece.
National & Kapodistrian University of Athens, Faculty of Pharmacy, Athens, Greece.
J Nutr Biochem. 2018 Sep;59:17-28. doi: 10.1016/j.jnutbio.2018.05.013. Epub 2018 Jun 5.
Oleuropein (OLE), a main constituent of olive, exhibits antioxidant and hypolipidemic effects, while it reduces the infarct size in chow- and cholesterol-fed rabbits. Peroxisome proliferator-activated receptor α (PPARα) has essential roles in the control of lipid metabolism and energy homeostasis. This study focused on the mechanisms underlying the hypolipidemic activity of OLE and, specifically, on the role of PPARα activation in the OLE-induced effect. Theoretical approach using Molecular Docking Simulations and luciferase reporter gene assay indicated that OLE is a ligand of PPARα. The effect of OLE (100 mg/kg, p.o., per day, ×6 weeks) on serum triglyceride (TG) and cholesterol levels was also assessed in adult male wild-type and Ppara-null mice. Molecular Docking Simulations, Luciferase reporter gene assay and gene expression analysis indicated that OLE is a PPARα agonist that up-regulates several PPARα target genes in the liver. This effect was associated with a significant reduction of serum TG and cholesterol levels. In contrast, OLE had no effect in Ppara-null mice, indicating a direct involvement of PPARα in the OLE-induced serum TG and cholesterol reduction. Activation of hormone-sensitive lipase in the white adipose tissue (WAT) and the liver of wild-type mice and up-regulation of several hepatic factors involved in TG uptake, transport, metabolism and clearance may also contribute in the OLE-induced TG reduction. In summary, OLE has a beneficial effect on TG homeostasis via PPARα activation. OLE also activates the hormone sensitive lipase in the WAT and liver and up-regulates several hepatic genes with essential roles in TG homeostasis.
橄榄叶提取物（OLE）是橄榄的主要成分，具有抗氧化和降血脂作用，同时还能减小低脂饮食和高胆固醇饮食兔的梗死面积。过氧化物酶体增殖物激活受体α（PPARα）在控制脂质代谢和能量平衡方面起着重要作用。本研究重点探讨了 OLE 降血脂活性的机制，特别是探讨了 PPARα 激活在 OLE 诱导作用中的作用。通过分子对接模拟和荧光素酶报告基因检测的理论方法表明，OLE 是 PPARα 的配体。还评估了 OLE（100mg/kg，口服，每天一次，连续 6 周）对成年雄性野生型和 Ppara 基因敲除小鼠血清甘油三酯（TG）和胆固醇水平的影响。分子对接模拟、荧光素酶报告基因检测和基因表达分析表明，OLE 是一种 PPARα 激动剂，可上调肝脏中的几种 PPARα 靶基因。这种作用与血清 TG 和胆固醇水平的显著降低有关。相比之下，OLE 在 Ppara 基因敲除小鼠中没有作用，表明 PPARα 直接参与了 OLE 诱导的血清 TG 和胆固醇降低。白色脂肪组织（WAT）和野生型小鼠肝脏中激素敏感脂肪酶的激活，以及几种参与 TG 摄取、转运、代谢和清除的肝脏因子的上调，也可能有助于 OLE 诱导的 TG 降低。总之，OLE 通过激活 PPARα 对 TG 稳态具有有益作用。OLE 还激活了 WAT 和肝脏中的激素敏感脂肪酶，并上调了几种在 TG 稳态中具有重要作用的肝脏基因。
