Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion.
A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca(2+) in response to glucose, and thereby glucose-induced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5-- islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5-- islets. Furthermore, exposure of LRP5++ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.
Fujino
Takahiro
T
Gene Research Center and Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University, Sendai 980-8574, Japan.
Asaba
Hiroshi
H
Kang
Man-Jong
MJ
Ikeda
Yukio
Y
Sone
Hideyuki
H
Takada
Shinji
S
Kim
Dong-Ho
DH
Ioka
Ryoichi X
RX
Ono
Masao
M
Tomoyori
Hiroko
H
Okubo
Minoru
M
Murase
Toshio
T
Kamataki
Akihisa
A
Yamamoto
Joji
J
Magoori
Kenta
K
Takahashi
Sadao
S
Miyamoto
Yoshiharu
Y
Oishi
Hisashi
H
Nose
Masato
M
Okazaki
Mitsuyo
M
Usui
Shinichi
S
Imaizumi
Katsumi
K
Yanagisawa
Masashi
M
Sakai
Juro
J
Yamamoto
Tokuo T
TT
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D002914:Chylomicrons / Q000378:metabolism; D004041:Dietary Fats; D020043:Genes, Essential; D005947:Glucose / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000097:blood / Q000235:genetics; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins; D008099:Liver / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D014158:Transcription, Genetic
D001786:Blood Glucose; D002914:Chylomicrons; D004041:Dietary Fats; D007328:Insulin; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D011973:Receptors, LDL; D015544:Inositol 1,4,5-Trisphosphate; D002784:Cholesterol; D005947:Glucose; D002118:Calcium