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Journal of Histochemistry and Cytochemistry, Vol. 48, 1357-1368, October 2000, Copyright © 2000, The Histochemical Society, Inc.

ARTICLE

Expression of the Type I Diabetes-associated Gene LRP5 in Macrophages, Vitamin A System Cells, and the Islets of Langerhans Suggests Multiple Potential Roles in Diabetes

David J. Figueroaa, J. Fred Hessa, Bonnie Kya, Sheryl D. Browna, Volker Sandigb, Anne Hermanowski–Vosatkac, Rebecca C. J. Twellsd, John A. Toddd, and Christopher P. Austina
a Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania
b Department of Virus and Cell Biology, Merck Research Laboratories, West Point, Pennsylvania
c Department of Endocrinology, Merck Research Laboratories, Rahway, New Jersey
d Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Cambridge, United Kingdom

Correspondence to: Christopher P. Austin, Dept. of Pharmacology, Merck Research Laboratories, WP26A-3000, PO Box 4, Sumneytown Pike, West Point, PA 19486. E-mail: christopher_austin@merck.com

LRP5 is a novel member of the low-density lipoprotein receptor family that is genetically associated with Type 1 diabetes. As a start to defining the normal function of LRP5 and to generate testable hypotheses of its potential role in Type 1 diabetes pathogenesis, we carried out an extensive expression analysis of this gene at the mRNA and protein levels in normal human, monkey, and mouse, as well as in non-obese diabetic (NOD) mice at several stages of diabetes development. In all species, expression of LRP5 was found in four functionally important cell types: the distributed mononuclear phagocyte system, the islets of Langerhans, vitamin A-metabolizing cells, and CNS neurons. Given the critical role of macrophages in the onset and progression of islet cell destruction in Type 1 diabetes and the hypothesized role of retinoids as modifiers of diabetes progression, these findings suggest that LRP5 may confer Type 1 diabetes risk by altering the normal functioning of one or more of these regulatory systems. Specifically, given that the LRP5 polymorphisms associated with diabetes are in the promoter region of the gene, alterations in LRP5 expression may be responsible for diabetes susceptibility and therefore may be potential targets for therapeutic intervention. (J Histochem Cytochem 48:1357–1368, 2000)

Key Words: Type I diabetes, low-density lipoprotein, LRP5, NOD mice, macrophages, retinoids


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