OVEREXPRESSION OF CHOLESTEROL 7-ALPHA-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 overexp ression of hepatic cholesterol 7 alpha-hydroxylase on low density lipo protein (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 decreas e in the rate of LDL cholesterol appearance in plasma (whole body LDL cholesterol transport) and a corresponding reduction in circulating LD L cholesterol levels. The increase in hepatic 7 alpha-hydroxylase acti vity necessary to achieve a 50% reduction in plasma LDL cholesterol co ncentrations was similar to 10-fold, In comparison, cholestyramine inc reased hepatic 7 alpha-hydroxylase activity similar to 3 fold and redu ced plasma LDL cholesterol concentrations by 17%, This study demonstra tes that augmentation of hepatic 7 alpha-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in anim als with a genetic absence of LDL receptors.