**3. Heterologous Expression of G5G8**

The first *ABCG5 ABCG8* transgenic strain contained an estimated 14 copies of the human gene, increased biliary cholesterol concentrations five to six-fold, and reduced susceptibility to experimental hypercholesterolemia and atherosclerosis [49,61]. A liverspecific transgenic failed to protect mice from atherosclerosis unless combined with the cholesterol absorption inhibitor ezetimibe [62,63]. The protective effects of G5G8 are presumably due to its role as the mediator of the final step of reverse cholesterol transport (RCT). Pharmacological stimuli of RCT, including ezetimibe and LXR and FXR agonists, require G5G8 to promote fecal neutral sterol loss and macrophage to feces RCT [50,64,65]. However, acute adenoviral-mediated overexpression of hepatic G5G8 fails to stimulate macrophage to feces RCT [56]. Further, adenoviral expression of G5G8 paradoxically increases plasma cholesterol, an effect blocked by ezetimibe [66]. This indicates that a substantial amount of biliary cholesterol is reabsorbed in the small intestine and illustrates the cooperative nature of hepatic and intestinal G5G8 in order to oppose hypercholesterolemia and promote RCT. This, however, is not the case for preventing phytosterolemia as tissue-selective deletion of intestinal or hepatic G5G8 results in only modest elevations in plasma phytosterols [67].
