Overexpression of Cholesterol 7α-Hydroxylase (CYP7A) in Mice Lacking the Low Density Lipoprotein (LDL) Receptor Gene

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 receptors (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, cholestyramine 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.