Tumor Necrosis Factor-α Induces Intestinal Insulin Resistance and Stimulates the Overproduction of Intestinal Apolipoprotein B48-Containing Lipoproteins

摘要

There is growing evidence suggesting intestinal insulin resistance and overproduction of apolipoprotein (apo) B48-containing chylomicrons in insulin-resistant states. In the current study, we investigated the potential role of the inflammatory cytokine tumor necrosis factor-α (TNF-α) in the development of insulin resistance and aberrant lipoprotein metabolism in the small intestine in a Syrian golden hamster model. TNF-α infusion decreased whole-body insulin sensitivity, based on in vivo euglycemic clamp studies in chow-fed hamsters. Analysis of intestinal tissue in TNF-α-treated hamsters indicated impaired phosphorylation of insulin receptor-β, insulin receptor sub-strate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal-related kinase-1/2, and Jun NH_2-terminal kinase. TNF-α infusion also increased intestinal production of total apoB48, triglyceride-rich lipoprotein apoB48, and serum triglyceride levels in both fasting and postprandial (fat load) states. The effects of TNF-α on plasma apoB48 levels could be blocked by the p38 inhibitor SB203580. Ex vivo experiments using freshly isolated enterocytes also showed TNF-α-induced p38 phosphorylation and intestinal apoB48 overproduction, effects that could be blocked by SB203580. Interestingly, TNF-α increased the mRNA and protein mass of intestinal microsomal triglyceride transfer protein without altering apoB mRNA levels. Enterocytes were found to have detectable levels of both TNF-α receptor types (p55 and p75), and antibodies against either of the two TNF-α receptors partially blocked the stimulatory effect of TNF-α on apoB48 production and p38 phosphorylation. In summary, these data suggest that intestinal insulin resistance can be induced in hamsters by TNF-α infusion, and it is accompanied by intestinal overproduction of apoB48-containing lipoproteins. TNF-α-induced stimulation of intestinal lipoprotein production appears to be mediated via TNF-α receptors and the p38 mitogen-activated protein kinase pathway.