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High density lipoprotein (HDL) is an atheroprotective element which is critical in the reverse cholesterol transport (RCT) pathway to eliminate excess cholesterol from the periphery of the body. A low plasma HDL cholesterol levels indicate a higher risk of getting cardiovascular diseases (CVD). Formation and metabolism of HDL largely rely on ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1) that are transporters to facilitate the efflux of cellular cholesterol to outside of cells. ABCA1 in the liver and small intestine is the major contributing factor for HDL formation. On the other hand, ABCA1 and ABCG1 present in macrophages contribute to cellular cholesterol homeostasis and protection against foam cell formation in artery. The objective of the study was to elucidate the regulatory mechanism for the expression of ABCA1 and ABCG1by fatty acids in HepG2 (a human hepatoma cell line), FHs 74 Int (a human small intestine epithelial cell line) and RAW264.7 macrophages. In all these cell lines, unsaturated fatty acids, but not saturated fatty acids, repressed the expression of ABCA1 and ABCG1 at the transcriptional and/or post-transcription levels in a cell type specific manner. The results of this study suggest the following mechanisms for the repressive effect of unsaturated fatty acids on the ABCA1 and ABCG1 expression: 1) ABCA1 in HepG2 and FHs 74 Int cells is inhibited by unsaturated fatty acids at the post-transcriptional level via calpain-independent mechanism; 2) ABCA1 and ABCG1 in RAW264.7 macrophages are repressed by unsaturated fatty acids at the transcriptional level by a liver X receptor-dependent mechanism and at the post-transcriptional level by increasing protein degradation.