title: PPARγ activation redirects macrophage cholesterol from fecal excretion to adipose tissue uptake in mice via SR-BI.
abstract: PPARγ agonists, used in the treatment of Type 2 diabetes, can raise HDL-cholesterol, therefore could potentially stimulate macrophage-to-feces reverse cholesterol transport (RCT). We aimed to test whether PPARγ activation promotes macrophage RCT in vivo. Macrophage RCT was assessed in mice using cholesterol loaded/(3)H-cholesterol labeled macrophages. PPARγ agonist GW7845 (20 mg/kg/day) did not change (3)H-tracer plasma appearance, but surprisingly decreased fecal (3)H-free sterol excretion by 43% (P<0.01) over 48h. Total free cholesterol efflux from macrophages to serum (collected from control and GW7845 groups) was not different, although ABCA1-mediated efflux was significantly higher with GW7845. To determine the effect of PPARγ activation on HDL cholesterol uptake by different tissues, the metabolic fate of HDL labeled with (3)H-cholesteryl ether (CE) was also measured. We observed two-fold increase in HDL derived (3)H-CE uptake by adipose tissue (P<0.005) with concomitant 22% decrease in HDL derived (3)H-CE uptake by the liver (P<0.05) in GW7845 treated wild type mice. This was associated with a significant increase in SR-BI protein expression in adipose tissue, but not liver. The same experiment in SR-BI knockout mice, showed no difference in HDL derived (3)H-CE uptake by adipose tissue or liver. In conclusion, PPARγ activation decreases the fecal excretion of macrophage derived cholesterol in mice. This is not due to inhibition of cholesterol efflux from macrophages, but rather involves redirection of effluxed cholesterol from liver towards adipose tissue uptake via SR-BI. This represents a novel mechanism for regulation of RCT and may extend the therapeutic implications of these ligands.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104, USA. s.e.s.toh.97@cantab.net
authors.forename: Sue-Anne
authors.initials: SA
authors.lastname: Toh
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Billheimer
authors.forename: Ilia
authors.initials: I
authors.lastname: Fuki
authors.forename: Snehal U
authors.initials: SU
authors.lastname: Naik
authors.forename: Colin
authors.initials: C
authors.lastname: Macphee
authors.forename: Max
authors.initials: M
authors.lastname: Walker
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005243:Feces; D005260:Female; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010080:Oxazoles / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists*; D051122:Scavenger Receptors, Class B / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010080:Oxazoles; D047495:PPAR gamma; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C401311:GW 7845; D014443:Tyrosine; D002784:Cholesterol