University of British Columbia, Faculty of Pharmaceutical Sciences, 2146 University Blvd, Vancouver, British Columbia, V6T 1Z3, Canada. thornton@zoology.ubc.ca
Pgp (P-glycoprotein, MDR1, ABCB1) is an energy-dependent drug efflux pump that is a member of the ATP-binding cassette (ABC) family of proteins. Preliminary studies have reported that nonspecific inhibitors of Pgp affect synthesis and esterification of cholesterol, putatively by blocking trafficking of cholesterol from the plasma membrane to the endoplasmic reticulum, and that relative increases in Pgp within a given cell type are associated with increased accumulation of cholesterol. Several key efflux proteins involved in the cholesterol metabolic pathway are transcriptionally regulated by the nuclear hormone liver X receptor (LXR). Therefore, to examine the interplay between P-glycoprotein and the cholesterol metabolic pathway, we utilized a high fat, normal cholesterol diet to upregulate LXRalpha without affecting dietary cholesterol. Our research has demonstrated that mice lacking in P-glycoprotein do not exhibit alterations in hepatic total cholesterol storage, circulating plasma total cholesterol levels, or total cholesterol concentration in the bile when compared to control animals on either a normal (25% calories from dietary fat) or high fat (45% calories from dietary fat) diet. However, p-glycoprotein deficient mice (Mdr1a-/-/1b-/-) exhibit increased hepatic LXRalpha protein expression and an elevation in fecal cholesterol concentration when compared to controls.