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

Abstract

The copolymer surfactant poloxamer 407 (P-407) has been used to induce a dose-controlled dyslipidemia in both mice and rats. Human macrophages cultured with P-407 exhibit a concentrationdependent 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. The present study investigated point(s) along this signaling 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 a) activate PPARα, or b) 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 dyslipidemia 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 dyslipidemia. 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.

The effect of poloxamer 407 on the functional properties of HDL in mice

“…a decrease in apoA‐1 and HDL and accelerated atherosclerosis). In view of the decrease in plasma apoA‐1 we observed in this investigation and previously, [35] future experiments will be directed at determining whether there has been substitution of serum amyloid A (SAA) for apoA‐1 in HDL (i.e. HDL that has been enriched with SAA) [36] …”

VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids

“…Although these data are consistent with our model, P-407 is not a specifi c inhibitor of lipase activity, and other effects may have confounded our results. However, P-407 does not inhibit fatty acid uptake or intracellular lipase activity and has no direct effects on PPAR-␣ function (22)(23)(24). Furthermore, LPL defi ciency decreases expression of PPAR-␣ target genes and mitigates cardiac myopathy induced by PPAR-␣ overexpression ( 15 ).…”

Influence of poloxamer 407 on fractional and subfractional composition of serum lipoproteins of mice

“…In the poloxamer 407 mouse model of atherosclerosis, the mechanism of cholesterol and TG elevation is associated with inhibition of cholesterol 7-hydroxylase and lipoprotein lipase, respectively [13], and not dependent on PPARα [14]. It was also shown that a single injection of poloxamer 407 administration to mice caused hypercholesterolemia by inducing transient cholesterolgenesis and down-regulating low-density lipoprotein receptor expression [6].…”