Document Detail


TNF-alpha decreases ABCA1 expression and attenuates HDL cholesterol efflux in the human intestinal cell line Caco-2.
MedLine Citation:
PMID:  20103810     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
HDL cholesterol levels are decreased in Crohn's disease, a tumor necrosis factor-alpha (TNF-alpha)-driven chronic inflammatory condition involving the gastrointestinal tract. ATP-binding cassette transporter A1 (ABCA1), one of several liver X receptor (LXR) target genes, is a cell surface transporter that mediates the rate-controlling step in HDL synthesis. The regulation of ABCA1 and HDL cholesterol efflux by TNF-alpha was investigated in the human intestinal cell line Caco-2. In response to cholesterol micelles or T0901317, an LXR nonsterol agonist, TNF-alpha decreased the basolateral efflux of cholesterol to apolipoprotein A1 (apoA1). TNF-alpha, by attenuating ABCA1 promoter activity, markedly decreased ABCA1 gene expression without attenuating the expression of LXR-alpha, LXR-beta, and most other LXR target genes, such as ABCG1, FAS, ABCG8, scavenger receptor-B1 (SR-B1), and apoC1. TNF-alpha also decreased ABCA1 mass by markedly enhancing the rate of ABCA1 degradation and modestly inhibiting its rate of synthesis. Inhibitors of the nuclear factor-kappaB (NF-kappaB) pathway, which is activated by TNF-alpha, partially reverse the effect of TNF-alpha on ABCA1 protein expression. The results suggest that TNF-alpha, the major cytokine implicated in the inflammation of Crohn's disease, decreases HDL cholesterol levels by attenuating the expression of intestinal ABCA1 and cholesterol efflux to apoA1.
Authors:
F Jeffrey Field; Kim Watt; Satya N Mathur
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-01-26
Journal Detail:
Title:  Journal of lipid research     Volume:  51     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-12     Completed Date:  2010-08-17     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1407-15     Citation Subset:  IM    
Affiliation:
Department of Internal, Medicine University of Iowa, Iowa City, IA 52242, USA. f-jeffrey-fi eld@uiowa.edu
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics*
Animals
Caco-2 Cells
Cholesterol, HDL / metabolism*
Gene Expression Regulation / drug effects*
Humans
Intestines / cytology*,  metabolism
NF-kappa B / metabolism
Orphan Nuclear Receptors / metabolism
Signal Transduction / drug effects
Tumor Necrosis Factor-alpha / pharmacology*
Grant Support
ID/Acronym/Agency:
DK-67132/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Cholesterol, HDL; 0/NF-kappa B; 0/Orphan Nuclear Receptors; 0/Tumor Necrosis Factor-alpha; 0/liver X receptor
Comments/Corrections

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