IngentaConnect The induction of atherogenic dyslipidaemia in poloxamer 407-treat...

Abstract:

The copolymer surfactant poloxamer 407 (P-407) has been used to induce a dose-controlled dyslipidaemia in both mice and rats. Human macrophages cultured with P-407 exhibit a concentration-dependent reduction in cholesterol efflux to apolipoprotein A1 (apoA1) due to down-regulation of the ATP-binding cassette transporter A1 (ABCA1). Peroxisome proliferator-activated receptor alpha (PPARα) can increase expression of liver X receptor alpha (LXRα) in macrophages and thereby promote the expression of ABCA1, which, in turn, mediates cholesterol efflux to apoA1. This study investigated point(s) along this signalling pathway at which P-407 might act to inhibit cholesterol efflux from macrophages. A transactivation assay was used to evaluate whether P-407 could either activate PPARα or block the activation of PPARα by an established PPARα agonist. P-407 was also evaluated for its potential to alter plasma lipid concentrations following its administration to both normal C57BL/6 and PPARα-deficient mice. P-407 was unable to modulate PPARα activity, as determined in cell-based transactivation assays. Moreover, P-407-induced dyslipidaemia occurred at the same rate and to the same extent in PPARα-deficient mice as was observed in C57BL/6 mice, suggesting no role for PPARα in P-407-mediated dyslipidaemia. Although PPARs are known to mediate the transcriptional regulation of the two major apolipoproteins associated with HDL (apoA1 and apoA2), P-407 treatment resulted in a similar decrease (∼30%) in the plasma concentration of apoA1 in both control and PPARα-deficient mice. Since our previous work demonstrated that P-407 was unable to abrogate the capacity of a known LXRα agonist to increase cholesterol efflux from macrophages, P-407 is likely to exert its effect, either directly or indirectly, on ABCA1, rather than on LXRα. On the basis of these findings it is concluded that PPARα does not mediate the P-407-dependent reduction in apoA1-facilitated cholesterol efflux from macrophages.

Document Type: Research article

DOI: 10.1211/jpp.60.6.0011

Affiliations: 1: Division of Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA 2: Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA, USA

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The induction of atherogenic dyslipidaemia in poloxamer 407-treated mice is not mediated through PPARα