Abstract
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.
Highlights
HDL cholesterol levels are decreased in Crohn’s disease, a tumor necrosis factor-␣ (TNF-␣)–driven chronic inflammatory condition involving the gastrointestinal tract
TNF-␣ attenuates ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux To address whether TNF-␣ alters cholesterol efflux to apolipoprotein A1 (apoA1), cells grown on micropore filters separating an upper and lower well were labeled with cholesterol overnight
The results of the present study clearly demonstrate that the proinflammatory cytokine TNF-␣ attenuates the expression of intestinal ABCA1, which results in a decrease in cholesterol efflux to apoA1
Summary
HDL cholesterol levels are decreased in Crohn’s disease, a tumor necrosis factor-␣ (TNF-␣)–driven chronic inflammatory condition involving the gastrointestinal tract. The results clearly demonstrate that TNF-␣ decreases the expression of ABCA1 in cultured intestinal cells, which leads to attenuation of cholesterol efflux in response to LXR activation. To estimate stability of ABCA1 mRNA, cells were incubated for 18 h with cholesterol micelles in the presence or absence of TNF-␣.
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