Severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis in mice lacking both low density lipoprotein receptor-related protein 5 and apolipoprotein E

Kenta Magoori, Man Jong Kang, Mitsuko R. Ito, Hajime Kakuuchi, Ryoichi X. Ioka, Akihisa Kamataki, Dong Ho Kim, Hiroshi Asaba, Satoshi Iwasaki, Yumiko A. Takei, Masako Sasaki, Shinichi Usui, Mitsuyo Okazaki, Sadao Takahashi, Masao Ono, Masato Nose, Juro Sakai, Takahiro Fujino, Tokuo T. Yamamoto

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

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 ∼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 ∼3-fold greater than those in the age-matched apoE-knockout mice. Furthermore, histological examination revealed highly advanced arthrosclerosis, 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.

Original languageEnglish
Pages (from-to)11331-11336
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number13
DOIs
Publication statusPublished - 2003 Mar 28

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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