Biliverdin reductase isozymes in metabolism

Abstract

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.

Keywords: BVRA; BVRB; bilirubin; biliverdin reductase; diabetes; heme oxygenase; obesity.

Figure I, Box 1. Alignment of human biliverdin reductase A and B isozymes

The alignment of BVRA and BVRB was done using the EMBOSS Pairwise Sequence Alignment (PROTEIN) software (https://www.ebi.ac.uk/Tools/psa/emboss_needle/). Identical regions are highlighted in green, similar regions are in yellow, and gray indicates no similarity between amino acid alignments.

Figure II, Box 2. Diagram of the differences in biliverdin reductase A and B signaling and enzymatic activity

BVRA and BVRB reduce biliverdin to bilirubin via their BVR domain. BVRB reduces only biliverdin IXβ, and BVRA has only enzymatic activity on biliverdin IXα. BVRB also has the ability to reduce flavins (FAD to FADH). BVRA has been shown to interact directly with the insulin receptor (IR) and proteins involved in the IR signaling cascade (MEK, ERK, and ELK). BVRA can also directly bind to the promoter of genes, such as HO-1 and regulate transcription. BVRB cannot bind directly to DNA, but does contain the domain that BVRA has been shown to interact with IR, suggesting a potential role in insulin signaling.

Figure 1. Domain structures of human biliverdin reductase A and B isozymes

Domain structural comparisons of BVRA and BVRB indicate that there is a similar kinase and catalytic domain for both isozymes. The major difference is in the C-terminus, where BVRA contains a bZip DNA binding domain, nuclear localization signaling, and nuclear export signal that are not located within BVRB.

Figure 2. BVR and bilirubin levels and their association with obesity

Increasing plasma levels of bilirubin are associated with decreased adipocyte size by scavenging free radicals (O-) and increasing production of anti-inflammatory adipokines (e.g. adiponectin), thus lowering the risk of type II diabetes. Obese patients have decreased levels of plasma total bilirubin (31), which results in increased free radicals and ROS, and in the enhancement of NF-kB mediated inflammation. This leads to adipocyte hypertrophy and increased production of pro-inflammatory adipokines (e.g. TNFα) that contribute to diabetes.

Figure 3. Involvement of BVRA in the insulin receptor signaling cascade

Activation of BVRA increases insulin receptor and PI3K signaling (39, 41), which enhances phosphorylation of Akt (8, 39, 41) and Glut4-mediated glucose uptake. BVRA inhibits the IRS-1 and PI3K interaction by phosphorylation of IRS-1. The serine 315 phosphorylation of IRS-1 uncouples it from the insulin receptor and inhibiting function (55). The SH2 domains in BVRA bind directly to PI3K to enhance pAkt signaling and glucose uptake (–41). Biliverdin activation of BVRA increases pAkt and glucose uptake, while the BVRA peptides have inhibitory and stimulatory roles. The BVRA peptides that target the SH2-binding domain inhibits glucose uptake.