Brain insulin signaling acts as a key regulator for gene expression and cellular metabolism, both of which sustain neuronal activity and synaptic plasticity mechanisms. Alterations in this pathway, known as brain insulin resistance, are associated with a higher risk of developing age-related cognitive decline and neurodegeneration. Studies from our group have uncovered the role of the enzyme biliverdin reductase A (BVR-A) in this process. BVR-A, beyond its activity in the degradation pathway of heme, is a novel regulator of insulin signaling. BVR-A is a direct target of the insulin receptor, similar to insulin receptor substrate-1 (IRS-1). The insulin receptor phosphorylates BVR-A on specific Tyr residues, activating it to function as a Ser/Thr/Tyr kinase. In addition, downstream from IRS-1, BVR-A works as a scaffold protein, promoting the translocation of GLUT4-containing vesicles to the plasma membrane (to increase glucose uptake in response to insulin), the AKT-mediated inhibition of GSK3β (which promotes cell survival), and the AMPK-mediated inhibition of MTOR (which is involved in autophagy). Our group's groundbreaking findings have revealed that oxidative stress-induced impairment of BVR-A is a key event driving brain insulin resistance development in Alzheimer's disease (AD). Conversely, rescuing BVR-A activity reduces oxidative stress levels and improves brain insulin signaling, both of which contribute to improved cognitive function in animal models of neurodegeneration. Overall, our data suggest that BVR-A represents a molecular link between oxidative stress and insulin signaling, and studies to further investigate its role in the development of neurodegenerative disorders are ongoing in our lab.
23 Marzo 2023
Prof. Eugenio Barone
Department of Biochemical Sciences
Sapienza University of Rome
eugenio.barone@uniroma1.it
Ora: 13:00
Aula: Aula A, CU010