Abstract
BackgroundSynthetic activators of peroxisome proliferator-activated receptors (PPARs) stimulate cholesterol removal from macrophages through PPAR-dependent up-regulation of liver × receptor α (LXRα) 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.MethodsRAW264.7 macrophages were treated without (control) or with LA or 13-HODE in the presence and absence of PPARα or PPARγ antagonists and determined protein levels of LXRα, ABCA1, ABCG1, SR-BI, PPARα and PPARγ and apolipoprotein A-I mediated lipid efflux.ResultsTreatment of RAW264.7 cells with 13-HODE increased PPAR-transactivation activity and protein concentrations of LXRα, 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 PPARα or PPARγ 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.Conclusion13-HODE induces cholesterol efflux from macrophages via the PPAR-LXRα-ABCA1/SR-BI-pathway.
Highlights
Synthetic activators of peroxisome proliferator-activated receptors (PPARs) stimulate cholesterol removal from macrophages through PPAR-dependent up-regulation of liver × receptor a (LXRa) and subsequent induction of cholesterol exporters such as ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type 1 (SR-BI)
Effects of 13-hydroxy octadecadienoic acid (13-HODE) and linoleic acid (LA) on PPAR transactivation activity and PPAR protein levels in RAW264.7 macrophages To study the effect of 13-HODE and LA on the activation of the PPAR signalling pathway in macrophages, RAW264.7 were transiently transfected with a reporter plasmid containing 3 copies of the consensus PPRE in front of a luciferase reporter and studied the stimulation of the reporter activity by 13-HODE and LA as well as by the synthetic peroxisome proliferator-activated receptor a (PPARa) agonist WY-14,643
The present study shows that 13-HODE moderately, but significantly lowers the cellular cholesterol content of macrophages while increasing the cholesterol content in the medium when apo-AI, the main apo of high density lipoprotein (HDL) particles, is present in the culture medium as an extracellular cholesterol acceptor
Summary
Synthetic activators of peroxisome proliferator-activated receptors (PPARs) stimulate cholesterol removal from macrophages through PPAR-dependent up-regulation of liver × receptor a (LXRa) and subsequent induction of cholesterol exporters such as ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type 1 (SR-BI). Besides targeting lipid catabolism in the liver and regulating plasma lipid concentrations, synthetic PPARa activators directly influence vascular function in a beneficial manner through negatively regulating the expression of pro-inflammatory genes in vascular cells such as endothelial cells, smooth muscle cells, and macrophages and inducing genes involved in macrophage cholesterol homeostasis [11,12,13] These direct atheroprotective together with the lipid lowering effects are largely responsible for the observation that pharmacological PPARa activators cause an inhibition of atherosclerosis development [14,15,16,17]. These findings suggest that OF exerts similar effects as pharmacological PPARa agonists
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
