Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, Building 307C, 10300 Baltimore Avenue, Beltsville, MD 20705-2350, USA.
Exp Biol Med (Maywood). 2010 Feb;235(2):199-205. doi: 10.1258/ebm.2009.009169.
The aim of this study was to determine whether systemic elevation of tumor necrosis factor (TNF)-alpha induces intestinal-derived apolipoprotein B (apoB)48-containing very low-density lipoprotein (VLDL) production in hamsters after fat loading and whether TNF-alpha disturbs the related mRNA expression in inflammatory, insulin and lipoprotein signaling pathways in primary enterocytes. In vivo TNF-alpha and Triton-WR1339 infusion, Western blotting and reverse transcriptase-polymerase chain reaction were combined to explore the mechanisms underlying intestinal overproduction of apoB48-containing chylomicrons and VLDL(1) particles by TNF-alpha. TNF-alpha infusion increased intestinal production of chylomicron and VLDL(1)-apoB48 in postprandial (fat load) states. Following TNF-alpha-treatment in enterocytes, there was enhanced gene expression of Il1alpha and beta, Il6 and Tnf and decreased mRNA levels of components of the insulin signaling pathway including the insulin receptor (Ir), Ir substrate-1 and 2, PI3 k, and Akt, but increased phosphatase and tensin homolog deleted on chromosome ten (Pten) protein and mRNA expression. TNF-alpha also induced Cd36 and peroxisome proliferators-activated receptor (Ppar)gamma expression, as well as microsomal triglyceride transfer protein (Mtp) protein and mRNA, but suppressed the sterol regulatory element binding protein (Srebp)1c protein and mRNA level. Systemic elevation of TNF-alpha stimulates the postprandial overproduction of apoB48-containing chylomicrons and VLDL(1) particles by disturbing intestinal gene expression of the inflammatory, insulin and lipoprotein pathways. These findings provide mechanistic links among the inflammatory factor, TNF-alpha, intestinal inflammatory/insulin insensitivity and the overproduction of intestinal apoB48-containing lipoproteins.
本研究旨在探讨脂肪负荷后全身性肿瘤坏死因子 (TNF)-α升高是否会诱导仓鼠肠道来源的载脂蛋白 B (apoB)48 富含极低密度脂蛋白 (VLDL) 的产生，以及 TNF-α是否会干扰初级肠细胞中与炎症、胰岛素和脂蛋白信号通路相关的相关 mRNA 表达。通过体内 TNF-α和 Triton-WR1339 输注、Western 印迹和逆转录聚合酶链反应相结合的方法，探讨了 TNF-α诱导肠道 apoB48 富含乳糜微粒和 VLDL(1)颗粒过度产生的机制。TNF-α输注增加了脂肪负荷后肠道乳糜微粒和 VLDL(1)-apoB48 的产生。在肠细胞中给予 TNF-α处理后，炎症信号通路中 Il1alpha 和 Il1beta、Il6 和 Tnf 的基因表达增强，胰岛素信号通路中包括胰岛素受体 (Ir)、Ir 底物-1 和 2、PI3 k 和 Akt 的 mRNA 水平降低，但磷酸酶和张力蛋白同源物缺失的十号染色体 (Pten) 蛋白和 mRNA 表达增加。TNF-α还诱导了 Cd36 和过氧化物酶体增殖物激活受体 (Ppar)γ的表达，以及微粒体甘油三酯转移蛋白 (Mtp) 蛋白和 mRNA 的表达，但抑制了固醇调节元件结合蛋白 (Srebp)1c 蛋白和 mRNA 水平。全身性 TNF-α升高通过干扰肠道炎症、胰岛素和脂蛋白通路的基因表达，刺激餐后 apoB48 富含乳糜微粒和 VLDL(1)颗粒的过度产生。这些发现为炎症因子 TNF-α、肠道炎症/胰岛素不敏感和肠道 apoB48 富含脂蛋白的过度产生之间提供了机制联系。
