13-hydroxy linoleic acid increases expression of the cholesterol transporters ABCA1, ABCG1 and SR-BI and stimulates apoA-I-dependent cholesterol efflux in RAW264.7 macrophages

Background: Synthetic activators of peroxisome proliferator-activated receptors (PPARs) stimulate cholesterol removal from macrophages through PPAR-dependent up-regulation of liver x receptor alpha (LXR alpha) and subsequent induction of cholesterol exporters such as ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type 1 (SR-BI). The present study aimed to test the hypothesis that the hydroxylated derivative of linoleic acid (LA), 13-HODE, which is a natural PPAR agonist, has similar effects in RAW264.7 macrophages. Methods: RAW264.7 macrophages were treated without (control) or with LA or 13-HODE in the presence and absence of PPAR alpha or PPAR gamma antagonists and determined protein levels of LXR alpha, ABCA1, ABCG1, SR-BI, PPAR alpha and PPAR gamma and apolipoprotein A-I mediated lipid efflux. Results: Treatment of RAW264.7 cells with 13-HODE increased PPAR-transactivation activity and protein concentrations of LXR alpha, ABCA1, ABCG1 and SR-BI when compared to control treatment (P < 0.05). In addition, 13-HODE enhanced cholesterol concentration in the medium but decreased cellular cholesterol concentration during incubation of cells with the extracellular lipid acceptor apolipoprotein A-I (P < 0.05). Pre-treatment of cells with a selective PPAR alpha or PPAR gamma antagonist completely abolished the effects of 13-HODE on cholesterol efflux and protein levels of genes investigated. In contrast to 13-HODE, LA had no effect on either of these parameters compared to control cells. Conclusion: 13-HODE induces cholesterol efflux from macrophages via the PPAR-LXR alpha-ABCA1/SR-BI-pathway.