Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion

Takahiro Fujino, Hiroshi Asaba, Man Jong Kang, Yukio Ikeda, Hideyuki Sone, Shinji Takada, Dong Ho Kim, Ryoichi X. Ioka, Masao Ono, Hiroko Tomoyori, Minoru Okubo, Toshio Murase, Akihisa Kamataki, Joji Yamamoto, Kenta Magoori, Sadao Takahashi, Yoshiharu Miyamoto, Hisashi Oishi, Masato Nose, Mitsuyo OkazakiShinichi Usui, Katsumi Imaizumi, Masashi Yanagisawa, Juro Sakai, Tokuo T. Yamamoto

Research output: Contribution to journalArticle

292 Citations (Scopus)

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 LRPS-deficient islets had a marked reduction in the levels of intracellular ATP and Ca2+ 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 Wnt/LRP5 signaling contributes to the glucose-induced insulin secretion in the islets.

Original languageEnglish
Pages (from-to)229-234
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number1
DOIs
Publication statusPublished - Jan 7 2003
Externally publishedYes

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Keywords

  • Chylomicron remnant
  • Diabetes
  • Insulin-like growth factor 1
  • Pancreatic β cells
  • Wnt protein

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Fujino, T., Asaba, H., Kang, M. J., Ikeda, Y., Sone, H., Takada, S., Kim, D. H., Ioka, R. X., Ono, M., Tomoyori, H., Okubo, M., Murase, T., Kamataki, A., Yamamoto, J., Magoori, K., Takahashi, S., Miyamoto, Y., Oishi, H., Nose, M., ... Yamamoto, T. T. (2003). Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proceedings of the National Academy of Sciences of the United States of America, 100(1), 229-234. https://doi.org/10.1073/pnas.0133792100