The ABCG5 ABCG8 (G5G8) sterol transporter promotes cholesterol secretion into bile and opposes dietary sterol absorption in the small intestine. An emerging body of literature suggests that G5G8 links sterol flux to various risk factors for metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD). Therapeutic approaches that accelerate G5G8 activity may augment reverse cholesterol transport (RCT) and provide beneficial effects in the prevention and treatment of cardiovascular and liver disease. Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant in part due to the reduced levels of hepatic G5G8 and biliary cholesterol. The underlying mechanisms responsible for the reduced G5G8 protein expression in these mice may provide a clue to the drug development for this target. My studies show that neither acute leptin replacement nor liver-specific deletion of leptin receptor alters G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy has no effect on G5G8 expression. Conversely, expression of the ER chaperone, GRP78, rescues G5G8 in db/db mice. Previous studies suggest an interdependent relationship between liver and intestine for cholesterol elimination. A combination therapy that increases G5G8-mediated biliary cholesterol secretion and simultaneously reduces intestinal absorption is likely to act additively in cholesterol elimination. My studies show that treatment with ursodiol (Urso) increases hepatic G5G8 protein and both biliary and fecal sterols in a dose-dependent manner. Ezetimibe (EZ), a potent inhibitor of intestinal cholesterol absorption, produces an additive and dose-dependent increase in fecal sterol excretion in the presence of Urso. However, the stimulatory effects of both Urso and Urso-EZ are not G5G8-dependent. Beyond increasing G5G8 protein expression and biliary cholesterol secretion, my studies also show that Urso stimulates ileal FGF15 expression in mice. Our data of the stimulated ileal FGF15 expression in LIRKO and reduced hepatic G5G8 protein levels in Atsb KO mice both indicate the previous unrecognized role of FGF15/19 in the regulation of G5G8 and its activity. Indeed, this is subsequently confirmed by our results from the direct test of recombinant human FGF19 on G5G8. Thus, FGF15/19 may provide an alternative strategy in drug development to target G5G8 activity and accelerate cholesterol elimination.