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Papers In Press, published online ahead of print February 16, 2004
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Medicine Dept., University of Washington, Seattle, WA 98195-6426
Corresponding Author: joram{at}u.washington.edu
Abnormal high-density lipoprotein (HDL) metabolism among patients with diabetes and insulin resistance may contribute to their increased risk of atherosclerosis. ATP-binding cassette transporter A1 (ABCA1) mediates the transport of cholesterol and phospholipids from cells to HDL apolipoproteins and thus modulates HDL levels and atherogenesis. Because fatty acids are elevated in diabetes, we examined their effects on ABCA1 activity in cultured macrophages. Either cAMP analogs or ligands for the liver X receptor/retinoid X receptor (LXR/RXR) system can induce Abca1 transcription in murine macrophages. When induced by cAMP, unsaturated but not saturated long-chain fatty acids inhibit apolipoprotein-mediated lipid efflux by destabilizing ABCA1 protein. Here we show that the saturated fatty acids palmitate and stearate also inhibit lipid efflux and destabilize ABCA1 when Abca1 is induced by LXR/RXR ligands instead of cAMP. These inhibitory effects were associated with an increased palmitate and stearate desaturation by stearoyl-CoA desaturase (SCD), one of the other gene products induced by LXR/RXR ligands. The SCD inhibitors conjugated linoleic acid and troglitazone nearly abolished ABCA1 destabilization by palmitate and stearate but had no effect on destabilization by linoleate. These results suggest that LXR/RXR ligands generate ABCA1-destabilizing monounsaturated fatty acids from their saturated precursors by activating SCD. Thus, with cholesterol-loaded macrophages exposed to saturated fatty acids, activated LXR/RXR may counteract the enhanced ABCA1 transcription by reducing the ABCA1 protein content.
Revised on February 6, 2004
Accepted on February 6, 2004
Liver X receptor-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ATP-binding cassette transporter A1
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