Liver-X-receptor-mediated increase in ATP-binding cassette transporter A1 expression is attenuated by fatty acids in CaCo- cells: effect on cholesterol efflux to high-density lipoprotein

The effect of fatty acids on LXR (liver X receptors)-mediated enhancement of ABCA1 (ATP-binding cassette transporter A1) expression and cholesterol efflux was investigated in human intestinal cells CaCo-2. LXR activation by T0901317 increased basolateral cholesterol efflux to lipoprotein particles isolated at a density of 1.21 g/ml or higher. Oleic and arachidonic acids attenuated the amount of cholesterol isolated from these particles. Stearic, linoleic and docosahexaenoic acids also decreased cholesterol efflux from basolateral membranes, with the polyunsaturated fatty acids being the most potent. Although oleic, arachidonic and docosahexaenoic acids modestly decreased ABCA1 mRNA levels in response to LXR activation, stearic and linoleic acids did not. Except for oleic acid, all fatty acids substantially attenuated an increase in ABCA1 mass secondary to LXR activation. Inhibiting acyl-CoA:cholesterol acyltransferase activity prevented the decrease in cholesterol efflux caused by oleic acid. Thus, in response to LXR activation, all fatty acids decreased the efflux of cholesterol from the basolateral membrane of CaCo-2 cells. Although modest suppression of ABCA1 gene expression by oleic, arachidonic and docosahexaenoic acids cannot be completely excluded as a mechanism, the predominant effect of fatty acids on ABCA1 expression and cholesterol efflux is at a post-transcriptional level.