Molecular Structure & Function, Research Institute, The Hospital for Sick Children, University of Toronto, Canada.
Am J Physiol Gastrointest Liver Physiol. 2011 Aug;301(2):G326-37. doi: 10.1152/ajpgi.00425.2010. Epub 2011 May 5.
Intestinal lipid dysregulation is a common feature of insulin-resistant states. The present study investigated alterations in gene expression of key proteins involved in the active absorption of dietary fat and cholesterol in response to development of insulin resistance. Studies were conducted in two diet-induced animal models of insulin resistance: fructose-fed hamster and high-fat-fed mouse. Changes in the mRNA abundance of lipid transporters, adenosine triphosphate cassette (ABC) G5, ABCG8, FA-CoA ligase fatty acid translocase P4, Niemann-Pick C1-Like1 (NPC1L1), fatty acid transport protein 4 (FATP4), and Scavenger Receptor Class B Type I (SR-BI), were assessed in intestinal fragments (duodenum, jejunum, and ileum) using quantitative real-time PCR. Of all the transporters evaluated, SR-B1 showed the most significant changes in both animal models examined. A marked stimulation of SR-B1 expression was observed in all intestinal segments examined in both insulin-resistant animal models. The link between SR-BI expression and intestinal lipoprotein production was then examined in the Caco-2 cell model. SR-B1 overexpression in Caco-2 cells increased apolipoprotein B (apoB) 100 and apoB48 secretion, whereas RNAi knock down of SR-B1 decreased secretion of both apoB100 and apoB48. We also observed changes in subcellular distribution of SR-B1 in response to exogenous lipid and insulin. Confocal microscopy revealed marked changes in SR-BI subcellular distribution in response to both exogenous lipids (oleate) and insulin. In summary, marked stimulation of intestinal SR-BI occurs in vivo in animal models of diet-induced insulin resistance, and modulation of SR-BI in vitro regulates production of apoB-containing lipoprotein particles. We postulate that apical and/or basolateral SR-BI may play an important role in intestinal chylomicron production and may contribute to chylomicron overproduction normally observed in insulin-resistant states.
肠道脂质失调是胰岛素抵抗状态的一个常见特征。本研究旨在探讨在胰岛素抵抗发展过程中，参与膳食脂肪和胆固醇主动吸收的关键蛋白的基因表达变化。该研究在两种胰岛素抵抗的饮食诱导动物模型中进行：果糖喂养的仓鼠和高脂肪喂养的小鼠。使用定量实时 PCR 评估肠道片段（十二指肠、空肠和回肠）中脂质转运体、三磷酸腺苷盒（ABC）G5、ABCG8、FA-CoA 连接酶脂肪酸转运蛋白 P4、尼曼-匹克 C1 样 1（NPC1L1）、脂肪酸转运蛋白 4（FATP4）和清道夫受体 B 型 I（SR-BI）的 mRNA 丰度变化。在所评估的所有转运体中，SR-B1 在两种检查的动物模型中均显示出最显著的变化。在两种胰岛素抵抗动物模型中，所有检查的肠道段均观察到 SR-B1 表达明显增加。然后在 Caco-2 细胞模型中检查了 SR-BI 表达与肠脂蛋白生成之间的联系。在 Caco-2 细胞中过表达 SR-B1 可增加载脂蛋白 B（apoB）100 和 apoB48 的分泌，而 RNAi 敲低 SR-B1 可减少 apoB100 和 apoB48 的分泌。我们还观察到 SR-B1 在细胞内的分布在对外源脂质和胰岛素的反应中的变化。共聚焦显微镜显示，SR-B1 亚细胞分布在外源脂质（油酸）和胰岛素的作用下发生明显变化。总之，在饮食诱导的胰岛素抵抗动物模型中，肠道 SR-BI 明显受到刺激，体外调节 SR-BI 可调节载脂蛋白 B 含脂蛋白颗粒的产生。我们假设顶端和/或基底外侧的 SR-BI 可能在肠乳糜微粒的产生中发挥重要作用，并可能导致胰岛素抵抗状态下通常观察到的乳糜微粒过度产生。
