The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling

Figure 1

(a) LRP1-dependent insulin signaling in peripheral tissues. Insulin stimulates LRP1 trafficking to the plasma membrane of hepatocytes, adipocytes, and neurons. GLUT2 in hepatocytes, GLUT4 in adipocytes, and GLUT3 and GLUT4 in neurons are translocated to the plasma membrane in an LRP1-dependent manner upon insulin stimulation. Upon binding to its receptor, insulin initiates signaling pathways that mediate GLUT4 translocation to the plasma membrane in a process regulated by LRP1 expressed in GLUT4 containing vesicles. Akt activation by insulin is crucial for this process as it causes AS160 phosphorylation at multiple sites and inactivates its GAP activity. AS160 is known to associate with the LRP1 cytoplasmic domain. Rab GTPase activation in turn stimulates GLUT4 translocation. (b) Glucose and insulin metabolism is modulated by LRP1 in the brain. Insulin production by cells in the brain is somewhat controversial, although insulin is delivered from the blood to the brain by receptor-mediated transcytosis. The insulin receptor rarely induces glucose uptake by brain cells. Instead, it has effects on feeding that are largely opposite to those produced by insulin in the periphery. CNS insulin also impacts cognition. In the brain, the most metabolically active organ, glucose acquisition is independent of insulin, and glucose transporter proteins (GLUTs) mediate glucose delivery from the blood to the brain through the blood-brain barrier (BBB). GLUT1 is detected exclusively in the endothelial cells of the BBB as well as all other neural cells (in a distinct molecular form different than BBB). GLUT3 is specifically expressed in neurons. GLUT4 is an insulin-sensitive transporter and is only expressed at lower levels in specialized neurons of the hippocampus and the cerebellum. The function of the BBB-localized LRP1 in actively removing Aβ from the brain is regulated by insulin levels. Through the endocytic function of LRP1, the BBB may act as the main sensor to report the nutritional status, especially the lipid composition of consumed food to special neurons which in turn regulate insulin signaling, as it was reported to be the case in Drosophila.

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