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Randomized Controlled Trial
. 2015 Nov 14;36(43):3020-2.
doi: 10.1093/eurheartj/ehv291. Epub 2015 Jun 25.

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

Amit V Khera  1 , John S Millar  2 , Giacomo Ruotolo  3 , Ming-Dauh Wang  3 , Daniel J Rader  4
Affiliations
Randomized Controlled Trial

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

Amit V Khera et al. Eur Heart J. .

Abstract

Aims: Fibrate medications weakly stimulate the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) and are currently employed clinically in patients with dyslipidaemia. The potent and selective agonist of PPAR-α 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-α agonist impacts cholesterol efflux capacity, a marker of HDL function.

Methods and results: 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 μg 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).

Conclusions: Potent stimulation of PPAR-α 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.

Keywords: Cholesterol efflux capacity; HDL-cholesterol; Lipid metabolism; PPAR-α.

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Figures

Figure 1
Figure 1
Relationship between change in apoA-I production rate and change in cholesterol efflux capacity after 8 weeks of therapy with either LY518674 or placebo.
See this image and copyright information in PMC

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