Overexpression of cholesterol 7alpha-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 7alpha-hydroxylase on low density lipoprotein (LDL) cholesterol transport in mice lacking LDL receptors (LDL receptor-/-). Primary overexpression of hepatic 7alpha-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 7alpha-hydroxylase activity necessary to achieve a 50% reduction in plasma LDL cholesterol concentrations was approximately 10-fold. In comparison, cholestyramine increased hepatic 7alpha-hydroxylase activity approximately 3-fold and reduced plasma LDL cholesterol concentrations by 17%. This study demonstrates that augmentation of hepatic 7alpha-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in animals with a genetic absence of LDL receptors.
Spady
D K
DK
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8887, USA. spady@utsw.swmed.edu
Cuthbert
J A
JA
Willard
M N
MN
Meidell
R S
RS
D000818:Animals; D001692:Biological Transport; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics*
D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002790:Cholesterol 7-alpha-Hydroxylase