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Insulin Facilitates the Hepatic Clearance of Plasma Amyloid β-Peptide (1–40) by Intracellular Translocation of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP-1) to the Plasma Membrane in Hepatocytes

Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan (C.T., S.O., T.T.); New Industry Creation Hatchery Center, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan (S.O, T.T.); and SORST of Japan Science and Technology Agency, Tokyo, Japan (S.O., T.T.)

The hepatic clearance of amyloid β-peptide (1–40) [Aβ(1–40)] from plasma, which is largely mediated by low-density lipoprotein receptor-related protein (LRP-1), is suggested to play a role in preventing Aβ(1–40) accumulation in the brain. Epidemiological investigations suggest a high incidence of cerebral Aβ deposition in insulin-resistant type II diabetes mellitus. The purpose of this study was to clarify the effect of insulin on the hepatic clearance of Aβ(1–40). LRP-1 expression on the hepatic plasma membrane was increased in a time-dependent manner by portal infusion of insulin and was 2.2-fold greater than that in nontreated controls after a 10-min infusion, whereas the expression in whole lysate was not affected by insulin treatment. The apparent hepatic uptake of [¹²⁵I]Aβ(1–40) was also induced by insulin in a time-dependent manner. The increase in [¹²⁵I]Aβ(1–40) uptake by insulin was concentration-dependent (EC₅₀ = 230 pM) and was completely abolished by receptor-associated protein (2 µM), an LRP-1 inhibitor. In conclusion, plasma insulin facilitates LRP-1 translocation to the hepatic plasma membrane from the intracellular pool, resulting in significant enhancement of hepatic Aβ(1–40) uptake from the circulating blood. The presently proposed mechanism would explain the epidemiological results demonstrating that type II diabetes mellitus is a risk factor of Alzheimer's disease.

Received for publication April 6, 2007.

Accepted for publication July 3, 2007.

Address correspondence to: Dr. Tetsuya Terasaki, Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: terasaki{at}mail.pharm.tohoku.ac.jp

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