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 7α-hydroxylase on low density lipoprotein (LDL) cholesterol transport in mice lacking LDL receptor (LDL receptor(-/-). Primary overexpression of hepatic 7α-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 7α-hydroxylase activity necessary to achieve a 50% reduction in plasma LDL cholesterol concentrations was ~10-fold. In comparison, cholesteryamine increased hepatic 7α-hydroxylase activity ~3- fold and reduced plasma LDL cholesterol concentrations by 17%. This study demonstrates that augmentation of hepatic 7α-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in animals with a genetic absence of LDL receptors.