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ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Diet, Genomics and Immunology Laboratory » Research » Publications at this Location » Publication #230951
Title: Elevation of tumor necrosis factor-alpha induces the overproduction of postprandial intestinal apolipoprotein B48-containing very low-density lipoprotein ........ the inflammatory and insulin signaling pathways in enterocytes

Author
item QIN, BOLIN - INTEGRITY NUTRACEUTICALS
item Dawson, Harry
item Anderson, Richard

Submitted to: Experimental Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/25/2008
Publication Date: 2/2/2010
Citation: Qin, B., Dawson, H.D., Anderson, R.A. 2010. Elevation of tumor necrosis factor-alpha induces the overproduction of postprandial intestinal apolipoprotein B48-containing very low-density lipoprotein ..... the inflammatory and insulin signaling pathways in enterocytes. Experimental Biology and Medicine(Maywood). 235(2):199-205.

Interpretive Summary: Factors that are a measure of inflammation, such as tumor necrosis factor (TNF-a), are present at increased concentrations in individuals who are insulin resistant and obese, and these biomarkers predict the development of type 2 diabetes and cardiovascular diseases. In the present study, we examined the acute effects of elevation of the inflammatory factor, TNF-a, on the production of combined fat and protein complexes involved in the transport and disposal of fats in hamsters. Hamsters were studied since the lipid metabolism of hamsters is similar to that of humans. TNF-a infusion induced whole-body insulin resistance in chow-fed hamsters and decreased activation of proteins involved in the function of insulin. TNF-a infusion also significantly increased production and decreased the breakdown of lipoproteins which are associated with increased risks of cardiovascular diseases. In summary, this study demonstrates that TNF-a impairs insulin signaling in hamsters accompanied by the overproduction of compounds which would increase the risks associated with cardiovascular diseases. This study will be of benefit to scientists working on the mechanism of cardiovascular disease associated with insulin resistance and may provide targets to help control associated diseases in humans.

Technical Abstract: The study proposed to determine if an acute elevation of TNF-a stimulates intestinal-derived apolipoprotein B (apoB) 48-containing very low density lipoprotein (VLDL) production in hamsters after fat loading, and if TNF-a disturbs the related mRNA expression of genes in the inflammatory and insulin-signaling pathways in cultured primary enterocytes. The research design and methods included the in vivo infusion of hamsters with TNF-a and Triton-WR1339, followed by Western blotting and RT-PCR measurements to explore the mechanisms underlying intestinal overproduction of apoB 48-containing chylomicrons and VLDL1 particles by TNF-a. The results of TNF-a infusion showed increased intestinal production of chylomicron and VLDL1-apoB48 in postprandial (fat loaded) state. Treatment of enterocytes with TNF-a enhanced gene expression of IL-1 a and ß, IL-6, and TNF-a, decreased mRNA levels of components of the insulin-signaling pathway including the insulin receptor (IR), IR substrate-1 and 2, PI3K, and Akt, and increased phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression. TNF-a also decreased the sterol regulatory element binding protein (SREBP)-1c mRNA and increased microsomal triglyceride transfer protein (MTTP) mRNA. It was concluded that systemic elevation of TNF-a stimulates the postprandial overproduction of intestinal apoB48-containing chylomicrons and VLDL1 particles by disturbing intestinal gene expression of the inflammatory and insulin-signaling pathways. These findings provide mechanistic links between TNF-a, intestinal inflammatory/insulin insensitivity, and intestinal apoB48 metabolism.