Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, Seville, Spain.
J Nutr. 2012 Feb;142(2):227-32. doi: 10.3945/jn.111.149963. Epub 2011 Dec 21.
The postprandial metabolism of dietary fats implies that the production of TG-rich lipoproteins (TRL) contributes to the progression of plaque development. TRL and their remnants cause rapid receptor-mediated monocyte/macrophage lipid engorgement via the cell surface apoB48 receptor (apoB48R). However, the mechanistic basis for apoB48 receptor (APOB48R) regulation by postprandial TRL in monocytes and macrophages is not well established. In this study, we investigated the effects of postprandial TRL from healthy volunteers on the expression of APOB48R mRNA and lipid uptake in human THP-1 monocytes and THP-1-derived macrophages. The expression of APOB48R mRNA was upregulated in THP-1 monocytes, but downregulated in THP-1-derived macrophages when treated with postprandial TRL (P < 0.05), in a dose- and time-dependent manner. TG and free cholesterol were dramatically increased in THP-1-derived macrophages (140 and 50%, respectively; P < 0.05) and in THP-1 monocytes (160 and 95%, respectively; P < 0.05). This lipid accumulation was severely decreased (~50%; P < 0.05) in THP-1-derived macrophages by small interfering RNA (siRNA) targeting of APOB48R. Using PPAR and retinoid X receptor (RXR) agonists, antagonists, and siRNA, our data indicate that PPARα, PPARγ, and RXRα are involved in postprandial TRL-induced APOB48R transcriptional regulation. Co-incubation with acyl-CoA synthetase or acyl-CoA:cholesterol acyltransferase inhibitors potentiated the effects of postprandial TRL on the expression of APOB48R mRNA in THP-1 monocytes and THP-1-derived macrophages. Our findings collectively suggest that APOB48R represents a molecular target of postprandial TRL via PPAR-dependent pathways in human THP-1 monocytes and macrophages and advance a potentially important link between postprandial metabolism of dietary fats and atherogenesis.
膳食脂肪的餐后代谢意味着富含甘油三酯的脂蛋白（TRL）的产生有助于斑块发展。TRL 及其残基通过细胞表面 apoB48 受体（apoB48R）引起快速的受体介导的单核细胞/巨噬细胞脂质充盈。然而，餐后 TRL 对单核细胞和巨噬细胞中 apoB48 受体（APOB48R）的调节机制尚未得到很好的确立。在这项研究中，我们研究了来自健康志愿者的餐后 TRL 对人 THP-1 单核细胞和 THP-1 衍生的巨噬细胞中 APOB48R mRNA 的表达和脂质摄取的影响。当用餐后 TRL 处理时，THP-1 单核细胞中 APOB48R mRNA 的表达上调，但 THP-1 衍生的巨噬细胞中下调（P <0.05），呈剂量和时间依赖性。TG 和游离胆固醇在 THP-1 衍生的巨噬细胞中显著增加（分别为 140%和 50%；P <0.05）和 THP-1 单核细胞（分别为 160%和 95%；P <0.05）。用针对 APOB48R 的小干扰 RNA（siRNA）处理后，这种脂质积累在 THP-1 衍生的巨噬细胞中严重减少（~50%；P <0.05）。使用 PPAR 和视黄酸 X 受体（RXR）激动剂、拮抗剂和 siRNA，我们的数据表明 PPARα、PPARγ 和 RXRα 参与了餐后 TRL 诱导的 APOB48R 转录调节。与酰基辅酶 A 合成酶或酰基辅酶 A：胆固醇酰基转移酶抑制剂共孵育增强了餐后 TRL 对 THP-1 单核细胞和 THP-1 衍生的巨噬细胞中 APOB48R mRNA 表达的影响。我们的研究结果表明，APOB48R 是人类 THP-1 单核细胞和巨噬细胞中餐后 TRL 通过 PPAR 依赖性途径的分子靶标，并为膳食脂肪的餐后代谢与动脉粥样硬化形成之间提供了一个潜在的重要联系。
