Departamento Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain.
J Nutr Biochem. 2013 Dec;24(12):2100-9. doi: 10.1016/j.jnutbio.2013.07.010.
Oleanolic acid is a triterpene widely distributed throughout the plant kingdom and present in virgin olive oil at a concentration of 57 mg/kg. To test the hypotheses that its long-term administration could modify hepatic gene expression in several animal models and that this could be influenced by the presence of APOA1-containing high-density lipoproteins (HDLs), diets including 0.01% oleanolic acid were provided to Apoe- and Apoa1-deficient mice and F344 rats. Hepatic transcriptome was analyzed in Apoe-deficient mice fed long-term semipurified Western diets differing in the oleanolic acid content. Gene expression changes, confirmed by reverse transcriptase quantitative polymerase chain reaction, were sought for their implication in hepatic steatosis. To establish the effect of oleanolic acid independently of diet and animal model, male rats were fed chow diet with or without oleanolic acid, and to test the influence of HDL, Apoa1-deficient mice consuming the latter diet were used. In Apoe-deficient mice, oleanolic acid intake increased hepatic area occupied by lipid droplets with no change in oxidative stress. Bmal1 and the other core component of the circadian clock, Clock, together with Elovl3, Tubb2a and Cldn1 expressions, were significantly increased, while Amy2a5, Usp2, Per3 and Thrsp were significantly decreased in mice receiving the compound. Bmal1 and Cldn1 expressions were positively associated with lipid droplets. Increased Clock and Bmal1 expressions were also observed in rats, but not in Apoa1-deficient mice. The core liver clock components Clock-Bmal1 are a target of oleanolic acid in two animal models independently of the diets provided, and this compound requires APOA1-HDL for its hepatic action.
齐墩果酸是一种广泛分布于植物界的三萜，在特级初榨橄榄油中浓度为 57 毫克/千克。为了验证其长期给药可以改变几种动物模型中肝脏基因表达的假说，以及这种作用是否受载脂蛋白 A1 富含高密度脂蛋白（HDL）的影响，给载脂蛋白 E 和载脂蛋白 A1 缺陷的小鼠以及 F344 大鼠提供了包含 0.01%齐墩果酸的饮食。在长期摄入不同齐墩果酸含量的半纯化西方饮食的载脂蛋白 E 缺陷小鼠中分析了肝脏转录组。通过逆转录定量聚合酶链反应（RT-qPCR）确认了基因表达变化，并探讨了其对肝脏脂肪变性的影响。为了在不依赖饮食和动物模型的情况下确定齐墩果酸的作用，给雄性大鼠喂食含或不含齐墩果酸的标准饮食，并用载脂蛋白 A1 缺陷小鼠来测试 HDL 的影响。在载脂蛋白 E 缺陷小鼠中，齐墩果酸摄入增加了肝内脂滴的面积，但氧化应激没有变化。Bmal1 和生物钟的另一个核心成分 Clock 以及 Elovl3、Tubb2a 和 Cldn1 的表达显著增加，而 Amy2a5、Usp2、Per3 和 Thrsp 的表达在接受该化合物的小鼠中显著降低。Bmal1 和 Cldn1 的表达与脂滴呈正相关。在大鼠中也观察到 Clock 和 Bmal1 表达增加，但在载脂蛋白 A1 缺陷小鼠中没有观察到。Clock-Bmal1 这两个核心肝脏时钟组件是两种动物模型中齐墩果酸的作用靶点，该化合物需要 APOA1-HDL 发挥其肝脏作用。
