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.

Keywords: Alzheimer’s disease; biliverdin reductase A; dementia; insulin signaling; metabolic disorders; neurodegenerative diseases; obesity; type 2 diabetes.

Figure 1

Known sites of BVR-A interaction in the insulin signaling pathway. Under physiological conditions, the activation of insulin signaling requires the binding of insulin to the insulin receptor (IR), which auto-phosphorylates on Tyr residues (Y, e.g., Tyr1158/1162/1163) and promotes the receptor tyrosine kinase-mediated phosphorylation of its substrate (IRS1) on specific Tyr residues (e.g., 632). In parallel, IR phosphorylates BVR-A on specific Tyr residues and activates BVR-A to function as Ser/Thr/Tyr kinase. Then, as part of a regulatory loop, BVR-A phosphorylates IRS1 on inhibitory Ser residues (S, e.g., Ser307) to avoid IRS1 aberrant activation in response to IR. Once activated, IRS1 works as a scaffold protein, driving the activation of the two main arms of the insulin signaling: (1) the Ras/Raf/MAPK pathway (ERK1/2) mainly involved in gene transcription; and (2) the PI3K/Akt axis that is critical for glucose uptake as well as for protein and lipid metabolism. Moreover, Akt promotes the phosphorylation of several targets, among which are: (1) GSK3β (on Ser9, inhibitory site), which has a role in energy production; and (2) mTOR (on Ser2448, activating site), which regulates protein synthesis and autophagy. Within both axes, BVR-A works as kinase or as scaffold protein facilitating: (1) ERK1/2 phosphorylation and the subsequent translocation in the nucleus and followed by the activation of Elk1; (2) the PDK1-mediated activation of Akt; (3) PDK1-mediated activation of the atypical PKCζ; (4) the Akt-mediated inhibition of GSK3β. Moreover, BVR-A was found to be essential for the AMPK-mediated inhibition of mTOR. Under condition of energy depletion, AMPK directly senses increases in AMP:ATP and ADP:ATP ratios, thus promoting the inhibition of mTOR to block the processes that deplete cellular ATP (e.g., protein synthesis and cell cycle progression, controlling cell size and preventing apoptosis). Moreover, AMPK is activated in response to nitrosative stress and that occurs independently of AMP/ATP levels. Conversely, reduced AMPK activation leads to mTOR hyper-activation. Arrows represent stimulation; lines represent inhibition. See text for more details.

Figure 2

Hypothesized mechanism through which impairment of BVR-A links brain insulin resistance with increased Aβ production in Alzheimer disease (AD). Under physiological conditions insulin receptor (IR) phosphorylates biliverdin reductase-A (BVR-A) on tyrosine (Y) residues promoting BVR-A kinase activity and scaffold functions. Through these activities BVR-A regulates the activation of insulin signalling. Moreover, BVR-A activation plays a critical role in the inhibition of beta secretase 1 (BACE1) recycling to the plasma membrane. The proposed path probably occurs at the level of the early endosomes where casein kinase 1(CK1)-mediated Ser phosphorylation of BACE1 favors BACE1 recycling to plasma membrane. Under physiological conditions, BVR-A inhibits CK1 activity, thus preventing the phosphorylation of BACE1 and the subsequent recycling at plasma membrane. Conversely, during the progression of Alzheimer disease (AD) pathology the increase of oxidative stress leads to reduced BVR-A Tyr phosphorylation and increased BVR-A nitration (3-NT) that (1) impairs the activation of the insulin signalling pathway and in parallel (2) promotes CK1-mediated BACE1 recycling at the plasma membrane, where BACE1 cleaves amyloid precursor protein (APP), leading to increased beta amyloid (Aβ) production. In turn, as in a vicious cycle, increased Aβ oligomers trigger the elevation of oxidative and nitrosative stress levels, which further impair BVR-A. Arrows: activation; lines: inhibition. Red arrows/lines, molecular pathways activated during AD.

Figure 3

Reduced BVR-A protein levels or impaired BVR-A activation occur with the progression of metabolic or neurodegenerative diseases. Reduced BVR-A protein levels or impaired BVR-A activation (reduced Tyr phosphorylation or increased nitration) are observed during the progression of either metabolic or neurodegenerative diseases and are associated with the dysfunction of insulin signaling.