Both the peroxisome proliferator-activated receptor delta agonist, GW0742, and ezetimibe promote reverse cholesterol transport in mice by reducing intestinal reabsorption of HDL-derived cholesterol.
Peroxisome proliferator-activated receptor delta (PPARdelta) agonism increases HDL cholesterol and has therefore the potential to stimulate macrophage-to-feces reverse cholesterol transport (RCT). To test whether PPARdelta activation promotes RCT in mice, in vivo macrophage RCT was assessed using cholesterol-loaded/3H-cholesterol-labeled macrophages injected intraperitoneally. PPARdelta agonist GW0742 (10 mg/kg per day) did not change 3H-tracer plasma appearance, but increased fecal 3H-free sterols excretion by 103% ( p < 0.005) over 48 hours. Total free cholesterol efflux from macrophages to serum (collected from both control and GW0742 groups) was not different, although ABCA1-mediated efflux was significantly higher with GW0742. The metabolic fate of HDL labeled with 3H- cholesteryl ether or 3H-cholesteryl oleate was also measured. While 3H-cholesteryl ether tissue uptake was unchanged, the 3H-tracer recovered in fecal free sterol fraction after 3H-cholesteryl oleate injection increased by 88% with GW0742 ( p < 0.0005). This was associated with a lower Niemann-Pick C1 like 1 (NPC1L1) mRNA expression in the small intestine ( p < 0.05). The same experiments in mice treated with ezetimibe, which blocks NPC1L1, showed a similar 2-fold increase in fecal free sterol excretion after labeled macrophages orHDL injection. In conclusion, PPARdelta activation enhances excretion of macrophage or HDL-derived cholesterol in feces through reduced NPC1L1 expression in mice, comparable to the effect of ezetimibe.
Briand
François
F
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Naik
Snehal U
SU
Fuki
Ilia
I
Millar
John S
JS
Macphee
Colin
C
Walker
Max
M
Billheimer
Jeffrey
J
Rothblat
George
G
Rader
Daniel J
DJ
D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D000069438:Ezetimibe; D005243:Feces / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000819:agonists*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D010636:Phenols; D013438:Sulfhydryl Compounds
D001384:Azetidines; D008076:Cholesterol, HDL; D000069438:Ezetimibe; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D047494:PPAR delta; D012333:RNA, Messenger; D013844:Thiazoles; C410800:NPC1L1 protein, human; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds