Open AccessBoth the Peroxisome Proliferator‐Activated Receptor δ Agonist, GW0742, and Ezetimibe Promote Reverse Cholesterol Transport in Mice by Reducing Intestinal Reabsorption of HDL‐Derived Cholesterol
Author(s) -
Briand François,
Naik Snehal U.,
Fuki Ilia,
Millar John S.,
Macphee Colin,
Walker Max,
Billheimer Jeffrey,
Rothblat George,
Rader Daniel J.
Publication year - 2009
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/j.1752-8062.2009.00098.x
Subject(s) - endocrinology , reverse cholesterol transport , medicine , liver x receptor , cholesterol , ezetimibe , abca1 , peroxisome proliferator activated receptor delta , sterol , chemistry , agonist , excretion , cholesteryl ester , peroxisome proliferator activated receptor , biology , receptor , lipoprotein , biochemistry , nuclear receptor , transporter , gene , transcription factor
Peroxisome proliferator‐activated receptor δ (PPARδ) agonism increases HDL cholesterol and has therefore the potential to stimulate macrophage‐to‐feces reverse cholesterol transport (RCT). To test whether PPAR™ activation promotes RCT in mice, in vivo macrophage RCT was assessed using cholesterol‐loaded/ 3 H‐cholesterol‐labeled macrophages injected intraperitoneally. PPAR™ agonist GW0742 (10 mg/kg per day) did not change 3 H‐tracer plasma appearance, but increased fecal 3 H‐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 3 H‐cholesteryl ether or 3 H‐cholesteryl oleate was also measured. While 3 H‐cholesteryl ether tissue uptake was unchanged, the 3 H‐tracer recovered in fecal free sterol fraction after 3 H‐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 or HDL injection. In conclusion, PPAR™ activation enhances excretion of macrophage or HDL‐derived cholesterol in feces through reduced NPC1L1 expression in mice, comparable to the effect of ezetimibe.