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Potent peroxisome proliferator-activated receptor-? agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome.


ABSTRACT: Fibrate medications weakly stimulate the nuclear receptor peroxisome proliferator-activated receptor-? (PPAR-?) and are currently employed clinically in patients with dyslipidaemia. The potent and selective agonist of PPAR-? LY518674 is known to substantially increase apolipoprotein A-I (apoA-I) turnover without major impact on steady-state levels of apoA-I or high-density lipoprotein-cholesterol (HDL-C). We sought to determine whether therapy with a PPAR-? agonist impacts cholesterol efflux capacity, a marker of HDL function.Cholesterol efflux capacity was measured at baseline and after 8 weeks of therapy in a randomized, placebo-controlled trial involving participants with metabolic syndrome treated with either LY518674 100 ?g daily (n = 13) or placebo (n = 15). Efflux capacity assessment was quantified using a previously validated ex vivo assay that measures the ability of apolipoprotein-B depleted plasma to mobilize cholesterol from macrophages. LY518674 led to a 15.7% increase from baseline (95% CI 3.3-28.1%; P = 0.02, P vs. placebo = 0.01) in efflux capacity. The change in apoA-I production rate in the active treatment arm was strongly linked to change in cholesterol efflux capacity (r = 0.67, P = 0.01).Potent stimulation of PPAR-? leads to accelerated turnover of apoA-I and an increase in cholesterol efflux capacity in metabolic syndrome patients despite no change in HDL-C or apoA-I levels. This finding reinforces the notion that changes in HDL-C levels may poorly predict impact on functionality and thus has implications for ongoing pharmacologic efforts to enhance apoA-I metabolism.

SUBMITTER: Khera AV 

PROVIDER: S-EPMC4644252 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

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