Vascular Biology, Robarts Research Institute, London, Ontario, Canada.
Diabetes. 2011 May;60(5):1446-57. doi: 10.2337/db10-0589. Epub 2011 Apr 6.
Increased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.
Lipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor-deficient mice (Ldlr(-/-)) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.
In HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal-related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr(-/-) mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid β-oxidation. Nobiletin did not activate any peroxisome proliferator-activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.
Nobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.
载脂蛋白 B100 血浆浓度升高常见于胰岛素抵抗患者，增加了动脉粥样硬化发展的风险。天然存在的多酚类化合物，包括类黄酮，具有抗动脉粥样硬化作用。本研究旨在评估多甲氧基黄酮诺必特对培养的人肝癌细胞（HepG2）和胰岛素抵抗及动脉粥样硬化小鼠模型中脂蛋白分泌的影响。
用诺必特或胰岛素孵育 HepG2 细胞，测定脂蛋白分泌情况。采用实时定量 PCR 评价 mRNA 丰度，并用 Western blot 证明细胞信号通路的激活。在喂食富含诺必特的西方饮食的 LDL 受体缺陷型（Ldlr(-/-)）小鼠中，记录代谢参数、基因表达、脂肪酸氧化、葡萄糖稳态和能量消耗。通过组织学分析定量动脉粥样硬化。
在 HepG2 细胞中，诺必特或胰岛素激活丝裂原活化蛋白激酶-细胞外信号调节激酶信号通路，增加 LDLR，降低 MTP 和 DGAT1/2 mRNA，导致 apoB100 分泌明显抑制。与胰岛素不同，诺必特不会诱导胰岛素受体或胰岛素受体底物-1磷酸化，也不会刺激脂肪生成。在高脂饮食喂养的 Ldlr(-/-)小鼠中，诺必特通过减少 VLDL-甘油三酯（TG）分泌来减轻血脂异常。诺必特可防止肝 TG 堆积，增加 Pgc1α 和 Cpt1α 的表达，并增强脂肪酸 β-氧化。诺必特不会激活任何过氧化物酶体增殖物激活受体（PPAR），表明其代谢作用与 PPAR 无关。诺必特增加了肝和外周胰岛素敏感性及葡萄糖耐量，并显著减轻了主动脉窦的动脉粥样硬化。
诺必特为治疗与胰岛素抵抗状态相关的血脂异常和动脉粥样硬化提供了新的思路。
