In:
American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 294, No. 5 ( 2008-05), p. G1120-G1129
Abstract:
Insulin-resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF)-α and hepatic overproduction of very low density lipoproteins (VLDL). Here, we provide evidence that increased TNF-α 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-α 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-α-treated hamsters indicated decreased tyrosine phosphorylation of insulin receptor (IR)-β, IR substrate-1 (Tyr), Akt (Ser 473 ), p38, ERK1/2, and JNK but increased serine phosphorylation of IRS-1 (Ser 307 ) and Shc. TNF-α 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-α-induced VLDL-apoB100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Unexpectedly, TNF-α 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-α 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.
Type of Medium:
Online Resource
ISSN:
0193-1857
,
1522-1547
DOI:
10.1152/ajpgi.00407.2007
Language:
English
Publisher:
American Physiological Society
Publication Date:
2008
detail.hit.zdb_id:
1477329-6
SSG:
12
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