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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/G1120    most recent 00407.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Qin, B. Articles by Adeli, K. PubMed PubMed Citation Articles by Qin, B. Articles by Adeli, K.

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