title: Tumor necrosis factor-alpha induces intestinal insulin resistance and stimulates the overproduction of intestinal apolipoprotein B48-containing lipoproteins.
abstract: There is growing evidence suggesting intestinal insulin resistance and overproduction of apolipoprotein (apo) B48-containing chylomicrons in insulin-resistant states. In the current study, we investigated the potential role of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the development of insulin resistance and aberrant lipoprotein metabolism in the small intestine in a Syrian golden hamster model. TNF-alpha infusion decreased whole-body insulin sensitivity, based on in vivo euglycemic clamp studies in chow-fed hamsters. Analysis of intestinal tissue in TNF-alpha-treated hamsters indicated impaired phosphorylation of insulin receptor-beta, insulin receptor substrate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal-related kinase-1/2, and Jun NH(2)-terminal kinase. TNF-alpha infusion also increased intestinal production of total apoB48, triglyceride-rich lipoprotein apoB48, and serum triglyceride levels in both fasting and postprandial (fat load) states. The effects of TNF-alpha on plasma apoB48 levels could be blocked by the p38 inhibitor SB203580. Ex vivo experiments using freshly isolated enterocytes also showed TNF-alpha-induced p38 phosphorylation and intestinal apoB48 overproduction, effects that could be blocked by SB203580. Interestingly, TNF-alpha increased the mRNA and protein mass of intestinal microsomal triglyceride transfer protein without altering apoB mRNA levels. Enterocytes were found to have detectable levels of both TNF-alpha receptor types (p55 and p75), and antibodies against either of the two TNF-alpha receptors partially blocked the stimulatory effect of TNF-alpha on apoB48 production and p38 phosphorylation. In summary, these data suggest that intestinal insulin resistance can be induced in hamsters by TNF-alpha infusion, and it is accompanied by intestinal overproduction of apoB48-containing lipoproteins. TNF-alpha-induced stimulation of intestinal lipoprotein production appears to be mediated via TNF-alpha receptors and the p38 mitogen-activated protein kinase pathway.
authors.affiliation: Division of Clinical Biochemistry, Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Bolin
authors.initials: B
authors.lastname: Qin
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Rita Kohen
authors.initials: RK
authors.lastname: Avramoglu
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
mesh_terms: D000818:Animals; D053283:Apolipoprotein B-48 / Q000097:blood / Q000378:metabolism*; D006224:Cricetinae; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008297:Male; D008647:Mesocricetus; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000502:physiology*
chemical_list: D053283:Apolipoprotein B-48; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D018124:Receptors, Tumor Necrosis Factor; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580