Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update

Abstract

Insulin signaling is a conserved pathway that orchestrates glucose and lipid metabolism, energy balance, and inflammation, and its dysregulation compromises the homeostasis of multiple systems. Insulin resistance is a shared hallmark of several metabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes, and has been associated with cognitive decline during aging and dementia. Numerous mechanisms promoting the development of peripheral and central insulin resistance have been described, although most of them were not completely clarified. In the last decades, several studies have highlighted that biliverdin reductase-A (BVR-A), over its canonical role in the degradation of heme, acts as a regulator of insulin signaling. Evidence from human and animal studies show that BVR-A alterations are associated with the aberrant activation of insulin signaling, metabolic syndrome, liver steatosis, and visceral adipose tissue inflammation in obese and diabetic individuals. In addition, recent findings demonstrated that reduced BVR-A levels or impaired BVR-A activation contribute to the development of brain insulin resistance and metabolic alterations in Alzheimer’s disease. In this narrative review, we will provide an overview on the literature by focusing on the role of BVR-A in the regulation of insulin signaling and how BVR-A alterations impact on cell dysfunctions in both metabolic and neurodegenerative disorders.

Dynamic Changes of BVRA Protein Levels Occur in Response to Insulin: A Pilot Study in Humans

“…During this test, PBMCs are exposed to insulin secreted naturally in response to rising glucose levels. The findings show that BVRA levels change over time, which supports the pleiotropic roles BVRA plays in insulin signaling [ 1 , 2 ]. Intriguingly, the extent of the variations of BVRA protein levels observed in PBMCs during the OGTT in the current study agrees with previous findings from both our group and others, showing that either a decrease or an increase in BVRA protein levels (in a range comprised between 20 and 60%, depending on the cell type/tissue evaluated) leads to an impaired or an increased activation of the insulin signaling, respectively [ 3 , 4 , 6 , 12 , 14 , 25 , 28 , 29 ].…”

“…To strengthen the hypothesis that intracellular BVRA protein levels change in response to insulin and that these changes might depend on the different roles BVRA plays within the insulin signaling pathway, e.g., a kinase for IRS1 and a scaffold required for AKT and MAPK activation [ 1 ], we evaluated the effect of 100 nM insulin administered to HEK293 cells for 15, 30, 60, and 120 min. The dose of insulin was selected based on our and others’ previous works showing that HEK293 cells are responsive to a such dose [ 3 , 28 ].…”

“…Biliverdin reductase-A (BVRA), mainly known as the enzyme responsible for bilirubin production in the degradation pathway of heme, has recently drawn attention for its role in regulating insulin signaling and participating in the maintenance of metabolic homeostasis [ 1 ]. BVRA is endowed with a dual-specificity serine/threonine/tyrosine (Ser/Thr/Tyr) kinase activity [ 2 , 3 ], a scaffold protein function [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ], and transcription functions [ 10 ] directly involved in the regulation of the cell redox metabolism and of the complex insulin signaling pathway at different levels.…”

Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer’s Disease

“…During AD progression, BVR-A Tyr phosphorylation is reduced, and BVR-A nitration is increased due to the elevated oxidative stress, a process that impairs the activation of the insulin signaling pathway and promotes CK1-mediated BACE1 recycling at the plasma membrane, where BACE1 cleaves APP and leads to elevated Aβ production. On the other hand, increased Aβ peptides trigger increased oxidative and nitrosative stress, leading to BVR-A impairment and resulting in a vicious cycle [ 444 ]. Moreover, studies have demonstrated that expression levels of the rate-limiting heme synthetic enzyme ALAS1 and the heme degradation enzyme HO-2 were selectively decreased in the hippocampi of AD brains.…”

Protocol for the assay of biliverdin by the recombinant protein HUG

“…While in the past biliverdin was considered merely an intermediate in the formation of bilirubin, its antioxidant, anti-in ammatory, and cytoprotective roles are now recognized, particularly in the immune system [3][4][5] . Alterations in the expression and activity of HO and BVR have been associated with various pathological conditions [6][7][8] mediated by activation or inhibition of speci c processes or metabolic pathways, such as cellular respiration or the production of proin ammatory cytokines. These effects can be due to increased cellular levels of BR and BV, which act as a redox couple with antioxidant properties 9,10 .…”