TNF-α decreases ABCA1 expression and attenuates HDL cholesterol efflux in the human intestinal cell line Caco-2

Abstract

HDL cholesterol levels are decreased in Crohn's disease, a tumor necrosis factor-α (TNF-α)-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-α was investigated in the human intestinal cell line Caco-2. In response to cholesterol micelles or T0901317, an LXR nonsterol agonist, TNF-α decreased the basolateral efflux of cholesterol to apolipoprotein A1 (apoA1). TNF-α, by attenuating ABCA1 promoter activity, markedly decreased ABCA1 gene expression without attenuating the expression of LXR-α, LXR-β, and most other LXR target genes, such as ABCG1, FAS, ABCG8, scavenger receptor-B1 (SR-B1), and apoC1. TNF-α also decreased ABCA1 mass by markedly enhancing the rate of ABCA1 degradation and modestly inhibiting its rate of synthesis. Inhibitors of the nuclear factor-κB (NF-κB) pathway, which is activated by TNF-α, partially reverse the effect of TNF-α on ABCA1 protein expression. The results suggest that TNF-α, 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. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.