Tumor Necrosis Factor-{alpha} Directly Stimulates the Overproduction of Hepatic Apolipoprotein B100-
March 29th, 2008 | by admin |Tumor Necrosis Factor-{alpha} Directly Stimulates the Overproduction of Hepatic Apolipoprotein B100-containing VLDL via Impairment of Hepatic Insulin Signaling.
Insulin resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF)-alpha and hepatic overproduction of very low density lipoproteins (VLDL). Here, we provide evidence that increased TNF-alpha 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-alpha infusion for 4 hours in chow-fed hamsters induced whole-body insulin resistance based on euglycemic hyperinsulinemic clamp studies. Immunoprecipitation and immunoblotting analysis of livers from TNF-alpha-treated hamsters indicated decreased tyrosine phosphorylation of insulin receptor (IR)-beta, IR substrate (IRS)-1 (Tyr), Akt (ser(473)), p38, ERK1/2, and JNK, but increased serine phosphorylation of IRS-1 (ser(307)) and Shc. TNF-alpha 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-alpha-induced VLDL-apoB100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Unexpectedly, TNF-alpha decreased the sterol regulatory element binding protein (SREBP)-1c mass and mRNA levels, but significantly increased microsomal triglyceride transfer protein (MTP) mass and mRNA levels in primary hepatocytes. In summary, these data provide direct evidence that TNF-alpha 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. Key words: Tumor Necrosis Factor, Liver, Lipoprotein, VLDL, Apolipoprotein B.
Qin B, Anderson RA, Adeli K.
USDA, Beltsville, Maryland, United States.