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PMID:12509515

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Citation

Fujino, T, Asaba, H, Kang, MJ, Ikeda, Y, Sone, H, Takada, S, Kim, DH, Ioka, RX, Ono, M, Tomoyori, H, Okubo, M, Murase, T, Kamataki, A, Yamamoto, J, Magoori, K, Takahashi, S, Miyamoto, Y, Oishi, H, Nose, M, Okazaki, M, Usui, S, Imaizumi, K, Yanagisawa, M, Sakai, J and Yamamoto, TT (2003) Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc. Natl. Acad. Sci. U.S.A. 100:229-34

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.

Links

PubMed PMC140935 Online version:10.1073/pnas.0133792100

Keywords

Animals; Blood Glucose/metabolism; Calcium/metabolism; Cholesterol/blood; Chylomicrons/metabolism; Dietary Fats; Genes, Essential; Glucose/pharmacology; Glucose Intolerance/blood; Glucose Intolerance/genetics; Hypercholesterolemia/blood; Hypercholesterolemia/genetics; Inositol 1,4,5-Trisphosphate/metabolism; Insulin/blood; Insulin/secretion; Islets of Langerhans/drug effects; Islets of Langerhans/secretion; LDL-Receptor Related Proteins; Liver/metabolism; Low Density Lipoprotein Receptor-Related Protein-5; Mice; Mice, Knockout; Polymerase Chain Reaction; Receptors, LDL/deficiency; Receptors, LDL/genetics; Transcription, Genetic

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:LRP5

acts_upstream_of_or_within

GO:0061178: regulation of insulin secretion involved in cellular response to glucose stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2448955

P

  • regulates_o_occurs_in:(CL:0000169)
  • regulates_o_occurs_in:(EMAPA:32927)

Seeded From UniProt

complete

MOUSE:LRP5

acts_upstream_of_or_within

GO:0061178: regulation of insulin secretion involved in cellular response to glucose stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2448955

P

  • regulates_o_occurs_in:(EMAPA:32927)
  • regulates_o_occurs_in:(CL:0000169)

Seeded From UniProt

complete

MOUSE:LRP5

acts_upstream_of_or_within

GO:0008203: cholesterol metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2448955

P

Seeded From UniProt

complete


See also

References

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