title: Potent peroxisome proliferator-activated receptor-α agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Yawkey 5B, Boston, MA 02114, USA avkhera@mgh.harvard.edu rader@mail.med.upenn.edu.
authors.forename: Amit V
authors.initials: AV
authors.lastname: Khera
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.affiliation: Cardiovascular Unit, Eli Lilly and Company, Indiannapolis, IN, USA.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Ruotolo
authors.affiliation: Cardiovascular Unit, Eli Lilly and Company, Indiannapolis, IN, USA.
authors.forename: Ming-Dauh
authors.initials: MD
authors.lastname: Wang
authors.affiliation: Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, Philadelphia, PA, USA avkhera@mgh.harvard.edu rader@mail.med.upenn.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D016632:Apolipoprotein A-I / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy*; D008875:Middle Aged; D047493:PPAR alpha / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000627:therapeutic use*; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; C479889:LY 518674; D047493:PPAR alpha; D011422:Propionates; D014230:Triazoles
keywords: Cholesterol efflux capacity; HDL-cholesterol; Lipid metabolism; PPAR-α