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

Clin Transl Sci. 2009 Apr;2(2):127-33. doi: 10.1111/j.1752-8062.2009.00098.x.


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.

Keywords: cholesterol; intestine; lipoproteins; reverse cholesterol transport.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azetidines / pharmacology*
  • Biological Transport / drug effects
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / metabolism*
  • Chromatography, High Pressure Liquid
  • Ezetimibe
  • Feces / chemistry
  • Female
  • Gene Expression Regulation / drug effects
  • Intestinal Absorption / drug effects*
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Kinetics
  • Liver / drug effects
  • Liver / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • PPAR delta / agonists*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Thiazoles / pharmacology*
  • Time Factors


  • Azetidines
  • Cholesterol, HDL
  • GW0742
  • Membrane Proteins
  • Membrane Transport Proteins
  • NPC1L1 protein, human
  • PPAR delta
  • RNA, Messenger
  • Thiazoles
  • Ezetimibe