Insulin facilitates the hepatic clearance of plasma amyloid beta-peptide (1 40) by intracellular translocation of low-density lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes.
The hepatic clearance of amyloid beta-peptide (1-40) [Abeta(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 Abeta(1-40) accumulation in the brain. Epidemiological investigations suggest a high incidence of cerebral Abeta 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 Abeta(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 [(125)I]Abeta(1-40) was also induced by insulin in a time-dependent manner. The increase in [(125)I]Abeta(1-40) uptake by insulin was concentration-dependent (EC(50) = 230 pM) and was completely abolished by receptor-associated protein (2 muM), 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 Abeta(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.
Tamaki
Chihiro
C
Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. terasaki@mail.pharm.tohoku.ac.jp
Ohtsuki
Sumio
S
Terasaki
Tetsuya
T
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D007328:Insulin; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)