Insulin induces the low density lipoprotein receptor‐related protein 1 (LRP1) degradation by the proteasomal system in J774 macrophage‐derived cells

Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic receptor, which binds and internalizes diverse ligands such as activated alpha(2)-macroglobulin (alpha(2)M*). LRP1 promotes intracellular signaling, which downstream mediates cellular proliferation and migration of different types of cells, including macrophages. Unlike the LDL receptor, LRP1 expression is not sensitive to cellular cholesterol levels but appears to be responsive to insulin. It has been previously demonstrated that insulin increases the cell surface presentation of LRP1 in adipocytes and hepatocytes, which is mediated by the intracellular PI(3)K/Akt signaling activation. The LRP1 protein distribution is similar to other insulin-regulated cell surface proteins, including transferring receptor (Tfr). However, in macrophages, the insulin effect on the LRP1 distribution and expression is not well characterized. Considering that macrophages play a central role in the pathogenesis of atherosclerosis, herein we evaluate the effect of insulin on the cellular expression of LRP1 in J774 macrophages-derived cells using Western blot and immunofluorescence microscopy. Our data demonstrate that insulin induces a significant decrease in the LRP1 protein content, without changing the specific mRNA level of this receptor. Moreover, insulin specifically affected the protein expression of LRP1 but not Tfr. The insulin-induced protein degradation of LRP1 in J774 cells was mediated by the activation of the PI(3)K/Akt pathway and proteasomal system by an enhanced ubiquitin-receptor conjugation. The decreased content of LRP1 induced by insulin affected the cellular internalization of alpha(2)M*. Thus, we propose that the protein degradation of LRP-1 induced by insulin in macrophages could have important effects on the pathogenesis of atherosclerosis.