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HORMONES AND SIGNALING

Tumor necrosis factor- directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling

¹Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; ²Beltsville Human Nutrition Research Center, United States Department of Agriculture, Beltsville, Maryland

Submitted 9 September 2007 ; accepted in final form 19 March 2008

Insulin-resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF)- and hepatic overproduction of very low density lipoproteins (VLDL). Here, we provide evidence that increased TNF- can directly stimulate the hepatic assembly and secretion of apolipoprotein B (apoB) 100-containing VLDL₁, using the Syrian golden hamster, an animal model that closely resembles humans in hepatic VLDL-apoB100 metabolism. In vivo TNF- infusion for 4 h in chow-fed hamsters induced whole-body insulin resistance on the basis of euglycemic hyperinsulinemic clamp studies. Immunoprecipitation and immunoblotting analysis of livers from TNF--treated hamsters indicated decreased tyrosine phosphorylation of insulin receptor (IR)-β, IR substrate-1 (Tyr), Akt (Ser⁴⁷³), p38, ERK1/2, and JNK but increased serine phosphorylation of IRS-1 (Ser³⁰⁷) and Shc. TNF- infusion also significantly increased hepatic production of total circulating apoB100 and VLDL-apoB100 in both fasting and postprandial (fat load) states. Ex vivo experiments, using cultured primary hepatocytes from hamsters, also showed TNF--induced VLDL-apoB100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Unexpectedly, TNF- decreased the sterol regulatory element-binding protein-1c mass and mRNA levels but significantly increased microsomal triglyceride transfer protein mass and mRNA levels in primary hepatocytes. In summary, these data provide direct evidence that TNF- induces whole-body insulin resistance and impairs hepatic insulin signaling accompanied by overproduction of apoB100-containing VLDL particles, an effect likely mediated via TNF receptor 2.

TNF-; liver; insulin resistance; lipid; lipoprotein; apoB

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