Biliverdin reductase isozymes in metabolism

doi:10.1016/j.tem.2015.02.001

Trends in Endocrinology & Metabolism

Volume 26, Issue 4, April 2015, Pages 212-220

https://doi.org/10.1016/j.tem.2015.02.001 Get rights and content

Highlights

•
BVR isozymes are major regulators of metabolic processes.
•
The BVR isozymes have structural differences that lead to variations in signaling.
•
BVRA directly regulates insulin receptor signaling.
•
Bilirubin treatments may function to prevent obesity and diabetes.

The biliverdin reductase (BVR) isozymes BVRA and BVRB are cell surface membrane receptors with pleiotropic functions. This review compares, for the first time, the structural and functional differences between the isozymes. They reduce biliverdin, a byproduct of heme catabolism, to bilirubin, display kinase activity, and BVRA, but not BVRB, can act as a transcription factor. The binding motifs present in the BVR isozymes allow a wide range of interactions with components of metabolically important signaling pathways such as the insulin receptor kinase cascades, protein kinases (PKs), and inflammatory mediators. In addition, serum bilirubin levels have been negatively associated with abdominal obesity and hypertriglyceridemia. We discuss the roles of the BVR isozymes in metabolism and their potential as therapeutic targets.

Introduction

In obese individuals, adipocyte expansion leads to increased inflammation as a result of elevated proinflammatory molecule secretion from adipose tissue, which leads to an exacerbated oxidative state that contributes to adipocyte hypertrophy [1]. Antioxidants may prove useful for reducing reactive oxygen species (ROS), preventing adipocyte expansion and chronic inflammation. Several studies have shown that activation of the heme oxygenase (HO) system reduces ROS, body weight, and blood glucose levels 2, 3, 4, 5, 6, 7. HO catabolizes heme to produce carbon monoxide (CO), iron, and the tetrapyrrolic bile pigment biliverdin, which is further reduced to the antioxidant bilirubin by the enzyme BVR. Recent studies have demonstrated that BVR, through production of bilirubin as well as direct signaling, may interact with the insulin receptor and thus affect insulin signaling [8], whereas serum total bilirubin levels have been negatively associated with hypertriglyceridemia and abdominal obesity [9]. However, the pathways by which BVR and its end product bilirubin signal in tissues like adipose and liver to help prevent insulin resistance and obesity are not well understood. Here we discuss the interactions and signaling pathways of the BVR system and its novel role as a metabolic regulator.

Section snippets

Structure and function

Specific structural sites of BVRA allow for the modulation of a diverse set of signaling pathways (Figure 1). The structure of BVRA can be divided into two major regions, the catalytic and the regulatory/DNA interaction domains. The N termini of BVRB and BVRA contain the catalytic domain and house a binding motif for NADP(H) and NAD(H) cofactors [10]. The C terminus of BVRA encompasses the domain structures for the basic leucine zipper (bZIP) to function as a transcription factor, as well as

BVR and bilirubin in metabolic disorders

In addition to being a potent antioxidant, bilirubin may also play a key role in obesity. Bilirubin can easily diffuse into the lipid environment [29] and moderately elevated plasma levels of bilirubin are associated with decreased abdominal obesity and lowered risk of metabolic syndrome (Figure 2) [30]. This was correlated with the observation that obese patients with elevated insulin and visceral adiposity have decreased levels of plasma total bilirubin [31]. Patients with elevated plasma

BVR and insulin signaling pathways

The most important mediator of metabolic processes is insulin, which is secreted after feeding from the pancreatic beta islet cells to initiate signal transduction pathways that increase glucose and fatty acid uptake by insulin-responsive tissues. In non-insulin-dependent diabetic patients, these processes become resistant in peripheral organs and result in insulin and glucose intolerance. Insulin causes autophosphorylation of tyrosine residues in the cytoplasmic portion of the transmembrane

BVR regulation of the PK family

The PK family regulates metabolic processes that include insulin actions in carbohydrate and fat metabolism, in muscle and adipose tissues, and in lipid synthesis in liver. The PKA isoforms are important for lipolytic actions in adipose and inhibition of insulin signaling, whereas the PKC class of serine/threonine kinases have diverse functions. BVRA is both a substrate and an activator of PKCβII, via phosphorylation and protein–protein interactions [57]. PKCβII may regulate insulin resistance

BVR regulation of inflammatory pathways

Autophosphorylation of specific serine/threonine residues stimulates the reductase activity of BVRA [20]. Phosphorylated BVRA regulates the expression of oxidative stress-responsive genes such as HO-1 and inducible nitric oxide synthase (iNOS) and interacts with members of the MAPK family including ERK1/2 11, 63, 64. These effects highlight BVRA as an early event in the adaptive response to stress, which has the capability to reduce ROS-induced damage and reduce inflammation. ROS enhance the

Concluding remarks and future perspectives

The diversity of functions associated with the BVR isozymes allows for their modulation of many downstream target molecules via protein–protein interactions, phosphorylation, and transcriptional regulation, which makes them potential targets for the development of new drugs in several areas including cardiovascular disease, metabolism, and cancer. Regarding metabolic disorders, the development of BVRA peptide agonists [8] could provide novel therapeutic agents for the treatment of type 2

Acknowledgments

This work was supported by the National Institutes of Health (NIH) PRIDE grant (HL106365) (T.D.H.), grants from the National Heart, Lung, and Blood Institute [K01HL-125445 (T.D.H.), PO1HL-051971, HL088421 (D.E.S.), and 1T32HL105324 (P.A.H)], and the National Institute of General Medical Sciences (P20GM-104357).

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Trends in Endocrinology & Metabolism

ReviewBiliverdin reductase isozymes in metabolism

Highlights

Introduction

Section snippets

Structure and function

BVR and bilirubin in metabolic disorders

BVR and insulin signaling pathways

BVR regulation of the PK family

BVR regulation of inflammatory pathways

Concluding remarks and future perspectives

Acknowledgments

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Life Sci.

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Obesity (Silver Spring)

Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade

Stem Cell Res. Ther.

Interdiction of the diabetic state in NOD mice by sustained induction of heme oxygenase: possible role of carbon monoxide and bilirubin

Antioxid. Redox Signal.

Heme oxygenase-1 induction remodels adipose tissue and improves insulin sensitivity in obesity-induced diabetic rats

Hypertension

The heme oxygenase system selectively modulates proteins implicated in metabolism, oxidative stress and inflammation in spontaneously hypertensive rats

Curr. Pharm. Des.

The heme oxygenase system suppresses perirenal visceral adiposity, abates renal inflammation and ameliorates diabetic nephropathy in Zucker diabetic fatty rats

PLoS ONE

Human biliverdin reductase-based peptides activate and inhibit glucose uptake through direct interaction with the kinase domain of insulin receptor

FASEB J.

Low serum total bilirubin concentrations are associated with increased prevalence of metabolic syndrome in Chinese

J. Diabetes

Review
Biliverdin reductase isozymes in metabolism