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 VLDL(1), using the Syrian golden hamster, an animal model that closely resembles humans in hepatic VLDL-apoB100 metabolism. In vivo TNF-alpha 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-alpha-treated hamsters indicated decreased tyrosine phosphorylation of insulin receptor (IR)-beta, IR substrate-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-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-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.
Qin
Bolin
B
Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Anderson
Richard A
RA
Adeli
Khosrow
K
D000818:Animals; D053299:Apolipoprotein B-100 / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D005215:Fasting / Q000097:blood / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D010766:Phosphorylation / Q000187:drug effects; D019518:Postprandial Period / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D053299:Apolipoprotein B-100; D002352:Carrier Proteins; D007328:Insulin; D008079:Lipoproteins, VLDL; D047889:Receptors, Tumor Necrosis Factor, Type II; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol