Unsaturated fatty acids repress the expression of ATP-binding cassette transporter A1 in HepG2 and FHs 74 Int cells

Adenosine triphosphate–binding cassette transporter A1 (ABCA1) plays a critical role in the formation and metabolism of high-density lipoproteins (HDLs). Adenosine triphosphate–binding cassette transporter A1 in the liver and small intestine, in particular, accounts for approximately 90% of plasma HDL cholesterol. Therefore, any alterations in the hepatic and intestinal expression of ABCA1 could have a large impact on HDL biogenesis. We tested the hypothesis that ABCA1 expression is regulated differentially by different types of fatty acids in the liver and small intestine. Human hepatoma HepG2 and human small intestine epithelial FHs 74 Int cells were used as an in vitro model. Cells were incubated with saturated and unsaturated fatty acids in the presence or absence of T0901317, a synthetic agonist of liver X receptor. Unsaturated fatty acids decreased ABCA1 protein levels at 100 μmol/L of concentration regardless of the agonist with a minimal effect on messenger RNA abundance. Incubation of HepG2 and FHs 74 Int cells with rottlerin, a protein kinase C δ (PKCδ) inhibitor, increased ABCA1 protein but did not abolish linoleic acid–induced decrease in ABCA1 protein levels. Depletion of PKCδ using small interfering RNA showed decreased ABCA1 protein levels in control, palmitic acid–, and linoleic acid–treated cells; but the repressive effect of linoleic acid was sustained. In conclusion, our results indicate that unsaturated fatty acids regulate ABCA1 expression in HepG2 and FHs 74 Int cells at the posttranscriptional level and PKCδ is likely to be involved in maintaining ABCA1 protein levels.