Received for publication April 6, 2007.
Revised June 7, 2007.
Accepted for publication July 3, 2007.

Insulin facilitates the hepatic clearance of plasma amyloid -peptide (1-40) by intracellular translocation of LRP-1 to the plasma membrane in hepatocytes

Abstract

The hepatic clearance of amyloid -peptide (1-40) (A(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 A(1-40) accumulation in the brain. Epidemiologic investigations suggest a high incidence of cerebral A 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 A(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 non-treated controls after a 10-min infusion, while the expression in whole lysate was not affected by insulin treatment. The apparent hepatic uptake of [¹²⁵I]A(1-40) was also induced by insulin in a time-dependent manner. The increase in [¹²⁵I]A(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 A(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.

Key words: Insulin, Receptor synthesis/trafficking, Recycling, Fluorescence techniques, Regulation - physiological, Regulation - post-transcriptional