Administration of a PPARalpha agonist increases serum apolipoprotein A-V levels and the apolipoprotein A-V/apolipoprotein C-III ratio.
Apolipoprotein A-V (apoA-V) first gained attention as a regulator of triglycerides through transgenic mouse studies. Furthermore, peroxisome proliferator-activated receptor alpha (PPARalpha) agonists such as fenofibrate increase apoA-V mRNA expression. Our group recently developed the first assay to quantitate serum apoA-V levels. Therefore, we sought to determine whether administration of a PPARalpha agonist would increase circulating apoA-V. Cynomolgus monkeys were dosed for 14 days with 0.3 mg/kg/day LY570977 L-lysine, a potent and selective PPARalpha agonist. Blood samples were drawn throughout the treatment period and after a 2 week washout. Administration of the PPARalpha agonist caused a 50% decrease in triglycerides that reversed at washout. Serum apoA-V concentrations increased 2-fold, correlated inversely with triglycerides, and were reversible at washout. The apoA-V/apoC-III ratio increased >2-fold, with this increase also reversible at washout. These data demonstrate for the first time that a PPARalpha agonist increases circulating apoA-V protein levels and the apoA-V/apoC-III ratio.
Schultze
Albert E
AE
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Alborn
William E
WE
Newton
Ronald K
RK
Konrad
Robert J
RJ
D000818:Animals; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A / Q000097:blood*; D001056:Apolipoproteins C / Q000097:blood*; D004353:Drug Evaluation, Preclinical; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D008252:Macaca fascicularis; D008297:Male; D047493:PPAR alpha / Q000819:agonists*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; D001056:Apolipoproteins C; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D014280:Triglycerides