Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/19/2008
Publication Date: 3/27/2008
Citation: Qin, B., Anderson, R.A., Khosrowl, A. 2008. Tumor necrosis factor-alpha impairs hepatic insulin signaling and stimulates the overproduction of hepatic apolipoprotein B100-containing very low density lipoproteins. American Journal of Physiology - Gastrointestinal and Liver Physiology. Interpretive Summary: There is growing evidence suggesting that type 2 diabetes and systemic inflammation are related, and that inflammation may contribute to insulin resistance. Moreover, biomarkers of inflammation, such as tumor necrosis factor (TNF-a), are present at increased concentrations in individuals who are insulin-resistant and obese, and these biomarkers predict the development of type 2 diabetes and cardiovascular disease. In the present study, we examined the potential role of TNF-a in insulin signaling and lipoprotein metabolism in the liver of Syrian golden hamsters. Hamsters were studied since the lipid metabolism of hamsters is similar to that of humans. TNF-a infusion induced whole-body insulin resistance in chow-fed hamsters and decreased activation of proteins involved in the function of insulin. TNF-a infusion also significantly increased production and decreased the breakdown of VLDL-lipoproteins, which are associated with increased risks of cardiovascular diseases. In summary, this study demonstrates that TNF-a impairs insulin signaling in hamsters accompanied by overproduction of VLDL particles which would increase the risks associated with cardiovascular diseases. This study will be of benefit to scientists working on the mechanism of cardiovascular disease associated with insulin resistance and potentially to the millions of people with diabetes and cardiovascular diseases.
Technical Abstract: Mechanisms underlying hepatic overproduction of apolipoprotein B (apoB) 100-containing very low density lipoproteins (VLDL) in insulin resistance induced by tumor necrosis factor (TNF)-a were investigated. In the present study, we examined the potential role of TNF-a in insulin signaling and lipoprotein metabolism in the livers of Syrian golden hamsters. In vivo TNF-a infusion induced whole-body insulin resistance in chow-fed hamsters. Analysis of livers in TNF-a-treated hamsters indicated decreased phosphorylation of insulin receptor (IR)-b, IR substrate (IRS)-1 (Tyr), Akt (ser473), p38, ERK1/2, and JNK, but increased phosphorylation of ser307 IRS-1 and Shc. TNF-a infusion also significantly increased hepatic production of total serum and VLDL-apoB100 in both fasting and postprandial (fat load) states. Ex vivo experiments, using cultured primary hepatocytes from hamsters, also showed TNF-a-induced VLDL-apoB100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Moreover, TNF-a decreased the sterol regulatory element binding protein-1c mRNA and increased microsomal triglyceride transfer protein mRNA without altering apoB mRNA levels in primary hepatocytes. In summary, we provide direct evidence that TNF-a impairs hepatic insulin signaling in hamsters accompanied by hepatic overproduction of apoB100-containing VLDL particles, an effect likely mediated via TNF receptor 2.