Differential effects of gemfibrozil and fenofibrate on reverse cholesterol transport from macrophages to feces in vivo.
Gemfibrozil and fenofibrate, two of the fibrates most used in clinical practice, raise HDL cholesterol (HDLc) and are thought to reduce the risk of atherosclerotic cardiovascular disease. These drugs act as PPARα agonists and upregulate the expression of genes crucial in reverse cholesterol transport (RCT). In the present study, we determined the effects of these two fibrates on RCT from macrophages to feces in vivo in human apoA-I transgenic (hApoA-ITg) mice. [(3)H]cholesterol-labeled mouse macrophages were injected intraperitoneally into hApoA-ITg mice treated with intragastric doses of fenofibrate, gemfibrozil or a vehicle solution for 17days, and radioactivity was determined in plasma, liver and feces. Fenofibrate, but not gemfibrozil, enhanced [(3)H]cholesterol flux to plasma and feces of female hApoA-ITg mice. Fenofibrate significantly increased plasma HDLc, HDL phospholipids, hApoA-I levels and phospholipid transfer protein activity, whereas these parameters were not altered by gemfibrozil treatment. Unlike gemfibrozil, fenofibrate also induced the generation of larger HDL particles, which were more enriched in cholesteryl esters, together with higher potential to generate preβ-HDL formation and caused a significant increase in [(3)H]cholesterol efflux to plasma. Our findings demonstrate that fenofibrate promotes RCT from macrophages to feces in vivo and, thus, highlight a differential action of this fibrate on HDL.
IIB Sant Pau. 08025 Barcelona, Spain.
Noemí
N
Rotllan
Gemma
G
Llaverías
Josep
J
Julve
Matti
M
Jauhiainen
Laura
L
Calpe-Berdiel
Cristina
C
Hernández
Rafael
R
Simó
Francisco
F
Blanco-Vaca
Joan Carles
JC
Escolà-Gil
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005243:Feces / Q000737:chemistry*; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation
D016632:Apolipoprotein A-I; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D002784:Cholesterol; D015248:Gemfibrozil; D011345:Fenofibrate