title: Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion.
abstract: 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.
authors.affiliation: Gene Research Center and Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University, Sendai 980-8574, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fujino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asaba
authors.forename: Man-Jong
authors.initials: MJ
authors.lastname: Kang
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sone
authors.forename: Shinji
authors.initials: S
authors.lastname: Takada
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Kim
authors.forename: Ryoichi X
authors.initials: RX
authors.lastname: Ioka
authors.forename: Masao
authors.initials: M
authors.lastname: Ono
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tomoyori
authors.forename: Minoru
authors.initials: M
authors.lastname: Okubo
authors.forename: Toshio
authors.initials: T
authors.lastname: Murase
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kamataki
authors.forename: Joji
authors.initials: J
authors.lastname: Yamamoto
authors.forename: Kenta
authors.initials: K
authors.lastname: Magoori
authors.forename: Sadao
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Hisashi
authors.initials: H
authors.lastname: Oishi
authors.forename: Masato
authors.initials: M
authors.lastname: Nose
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Okazaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Usui
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
authors.forename: Tokuo T
authors.initials: TT
authors.lastname: Yamamoto
mesh_terms: 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
chemical_list: 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