Severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis in mice lacking both low density lipoprotein receptor-related protein 5 and apolipoprotein E.
LDL receptor-related protein 5 (LRP5) plays multiple roles, including embryonic development and bone accrual development. Recently, we demonstrated that LRP5 is also required for normal cholesterol metabolism and glucose-induced insulin secretion. To further define the role of LRP5 in the lipoprotein metabolism, we compared plasma lipoproteins in mice lacking LRP5, apolipoprotein E (apoE), or both (apoE;LRP5 double knockout). On a normal chow diet, the apoE;LRP5 double knockout mice (older than 4 months of age) had approximately 60% higher plasma cholesterol levels compared with the age-matched apoE knockout mice. In contrast, LRP5 deficiency alone had no significant effects on the plasma cholesterol levels. High performance liquid chromatography analysis of plasma lipoproteins revealed that cholesterol levels in the very low density lipoprotein and low density lipoprotein fractions were markedly increased in the apoE;LRP5 double knockout mice. There were no apparent differences in the pattern of apoproteins between the apoE knockout mice and the apoE;LRP5 double knockout mice. The plasma clearance of intragastrically loaded triglyceride was markedly impaired by LRP5 deficiency. The atherosclerotic lesions of the apoE;LRP5 double knockout mice aged 6 months were approximately 3-fold greater than those in the age-matched apoE-knockout mice. Furthermore, histological examination revealed highly advanced atherosclerosis, with remarkable accumulation of foam cells and destruction of the internal elastic lamina in the apoE;LRP5 double knockout mice. These data suggest that LRP5 mediates both apoE-dependent and apoE-independent catabolism of plasma lipoproteins.
Magoori
Kenta
K
Tohoku University Gene Research Center, Aoba, Sendai 981-8555, Japan.
Kang
Man-Jong
MJ
Ito
Mitsuko R
MR
Kakuuchi
Hajime
H
Ioka
Ryoichi X
RX
Kamataki
Akihisa
A
Kim
Dong-Ho
DH
Asaba
Hiroshi
H
Iwasaki
Satoshi
S
Takei
Yumiko A
YA
Sasaki
Masako
M
Usui
Shinichi
S
Okazaki
Mitsuyo
M
Takahashi
Sadao
S
Ono
Masao
M
Nose
Masato
M
Sakai
Juro
J
Fujino
Takahiro
T
Yamamoto
Tokuo T
TT
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001161:Arteriosclerosis / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004041:Dietary Fats / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006937:Hypercholesterolemia / Q000235:genetics*; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D004041:Dietary Fats; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D011973:Receptors, LDL