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 3 H-cholesteryl ether (CE) was also measured. We observed two-fold increase in HDL derived 3 H-CE uptake by adipose tissue ( P 3 H-CE uptake by the liver ( P 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.