Major Involvement of Low-Density Lipoprotein Receptor-Related Protein 1 in the Clearance of Plasma Free Amyloid -Peptide by the Liver
Authors: Tamaki, Chihiro; Ohtsuki, Sumio; Iwatsubo, Takeshi; Hashimoto, Tadafumi; Yamada, Kaoru; Yabuki, Chiori; Terasaki, Tetsuya
Source: Pharmaceutical Research, Volume 23, Number 7, July 2006 , pp. 1407-1416(10)
Abstract:To identify the molecules responsible for amyloid -peptide (1–40) (A(1–40)) uptake by the liver, which play a major role in the systemic clearance of A(1–40).
The liver uptake index method was used to examine the mechanisms of A(1–40) uptake by the liver in vivo.
[125I]A(1–40) uptake by the rat liver was concentration-dependent (50% saturation concentration = 302 nM). The inhibitory spectrum of A fragments indicated that 17–24 in A (LVFFAEDV) was the putative sequence responsible for hepatic A(1–40) uptake. Receptor-associated protein (RAP) inhibited [125I]A(1–40) uptake by 48%. RAP-deficient mice, in which low-density lipoprotein receptor-related protein 1 (LRP-1) expression was suppressed, showed a 46% reduction in [125I]A(1–40) uptake by the liver. siRNA-mediated suppression of LRP-1 expression in the liver resulted in a reduction in [125I]A(1–40) uptake by 64%. Both the expression of LRP-1 in the liver and the hepatic A(1–40) uptake were significantly reduced in 13-month-old rats compared with 7-week-old rats.
LRP-1 is the major receptor responsible for the saturable uptake of plasma free A(1–40) by the liver. Reduction of LRP-1 expression will play a role in the age-related reduction in hepatic A(1–40) clearance.
Document Type: Research Article
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Publication date: July 1, 2006