Overexpression of cholesterol 7α-hydroxylase (CYP7A) in mice lacking the low density lipoprotein (LDL) receptor gene -: LDL transport and plasma LDL concentrations are reduced

This study was undertaken to determine the effect of transient overexpression of hepatic cholesterol 7 alpha-hydroxylase on low density lipoprotein (LDL) cholesterol transport in mice lacking LDL receptors (LDL receptor(-/-)). Primary overexpression of hepatic 7 alpha-hydroxylase in LDL receptor(-/-) mice was accompanied by a dose-dependent decrease in the rate of LDL cholesterol appearance in plasma (whole body LDL cholesterol transport) and a corresponding reduction in circulating LDL cholesterol levels. The increase in hepatic 7 alpha-hydroxylase activity necessary to achieve a 50% reduction in plasma LDL cholesterol concentrations was similar to 10-fold, In comparison, cholestyramine increased hepatic 7 alpha-hydroxylase activity similar to 3 fold and reduced plasma LDL cholesterol concentrations by 17%, This study demonstrates that augmentation of hepatic 7 alpha-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in animals with a genetic absence of LDL receptors.