Affinage

BLVRA

Biliverdin reductase A · UniProt P53004

Length
296 aa
Mass
33.4 kDa
Annotated
2026-04-28
28 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BLVRA encodes biliverdin reductase A, a dual-function protein that serves both as an NADH/NADPH-dependent oxidoreductase converting biliverdin IXα to bilirubin and as a signaling scaffold that integrates antioxidant defense, metabolic regulation, and inflammatory signaling. The enzyme catalyzes biliverdin reduction via B-face (pro-S) hydride transfer with burst kinetics, and its catalytic activity is essential for hepatocyte and adipocyte antioxidant defense, mitochondrial biogenesis, and lipid homeostasis (PMID:9359830, PMID:31422074, PMID:32131495). Beyond its enzymatic role, BVRA associates with mTORC2 pathway components (Akt, PKCζ, AMPK) to mediate anti-inflammatory signaling in leukocytes and macrophages, specifically promoting IL-10 production and suppressing TLR4-driven inflammation, and regulates the AMPK/mTOR/autophagy axis in brain (PMID:31065010, PMID:26393580, PMID:32727065). Homozygous loss-of-function mutations in BLVRA cause accumulation of biliverdin IXα during cholestasis, establishing the gene as necessary for bilirubin production in humans (PMID:21278388).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1983 Medium

    The question of whether the dual-cofactor (NADH/NADPH) biliverdin reductase activity in humans arises from one or multiple gene products was resolved: a single BLVRA locus on chromosome 7p14-cen encodes a monomeric enzyme with both activities.

    Evidence Gel electrophoresis with chromogenic staining in somatic cell hybrid panels

    PMID:6838484

    Open questions at the time
    • No structural data on cofactor binding sites
    • Chromosome mapping based on somatic cell hybrids only
  2. 1997 High

    The catalytic mechanism of BVR-A was defined at the stereochemical level: the enzyme transfers the pro-S (B-face) hydride from NADH to biliverdin with pre-steady-state burst kinetics, and this mechanism is intrinsic to the monomeric BVR-A domain.

    Evidence Recombinant GST-BVR-A with stereospecific [4-³H]NADH labeling and pre-steady-state kinetics in vitro

    PMID:9359830

    Open questions at the time
    • No crystal structure to identify active-site residues
    • Mechanism characterized with rat ortholog, not human protein
  3. 2011 High

    Direct human genetic evidence established BLVRA as essential for bilirubin production: a homozygous nonsense mutation (p.Ser44X) abolished catalytic activity and caused biliverdin accumulation during cholestasis, confirmed by reconstitution in two heterologous systems.

    Evidence Site-directed mutagenesis, expression in hepatoma cells and Xenopus oocytes, functional enzymatic assay

    PMID:21278388

    Open questions at the time
    • Only one family reported
    • No rescue experiment in patient-derived cells
  4. 2015 Medium

    BVRA was placed upstream of anti-inflammatory IL-10 signaling in macrophages, extending its role beyond biliverdin reduction to immune regulation: overexpression increased and knockdown decreased IL-10 without affecting TNF-α.

    Evidence Adenoviral overexpression and siRNA knockdown in bone marrow-derived macrophages with ELISA; validated in renal ischemia-reperfusion model

    PMID:26393580

    Open questions at the time
    • Molecular mechanism linking BVRA to IL-10 transcription not identified
    • Single lab, no independent replication
  5. 2018 Medium

    A post-transcriptional regulatory axis was established: miR-222 directly targets the BLVRA 3′-UTR to repress BVRA protein, and BVRA levels are functionally required for erythroid differentiation.

    Evidence Luciferase 3′-UTR reporter, miRNA mimic/inhibitor, siRNA knockdown, erythroid differentiation assay in K562 cells and CD34+ HPCs

    PMID:29368338

    Open questions at the time
    • Mechanism by which BVRA promotes erythroid differentiation unclear
    • Relevance to in vivo erythropoiesis not tested
  6. 2019 Medium

    The signaling scaffold function of BVRA was molecularly defined: BVRA physically associates with AMPK, PKCζ, and TSC1/2 and mediates mTORC2-dependent phosphorylation of Akt and PKCζ upon biliverdin stimulation, establishing a BVRA/mTORC2 anti-inflammatory axis suppressed by TLR4 activation.

    Evidence Co-immunoprecipitation, phospho-protein immunoblotting, pharmacological inhibition (Torin, PP242, PKCζ peptide), validated in cardiopulmonary bypass patient samples

    PMID:31065010

    Open questions at the time
    • Direct binding surfaces between BVRA and mTORC2 components not mapped
    • Co-IP associations not confirmed by reciprocal endogenous pulldowns in all cases
  7. 2019 Medium

    Genetic ablation in hepatocytes demonstrated that BVRA's enzymatic activity is required for antioxidant defense, mitochondrial biogenesis, and lipid homeostasis, extending its known role beyond bilirubin production to organelle maintenance.

    Evidence CRISPR-Cas9 knockout in hepa1c1c7 cells with ROS, mitochondrial function, and lipid accumulation assays

    PMID:31422074

    Open questions at the time
    • Not established whether phenotypes are rescued by exogenous bilirubin versus require BVRA protein per se
    • Single cell line
  8. 2020 Medium

    Tissue-specific knockout revealed BVRA is essential for white adipose tissue insulin signaling and mitochondrial function in vivo, linking it to metabolic homeostasis: adipose-specific deletion reduced pAKT, Glut4, browning genes, and mitochondrial number.

    Evidence Adipose-specific conditional Blvra knockout mouse, phospho-AKT immunoblotting, histology, qRT-PCR

    PMID:32131495

    Open questions at the time
    • Whether enzymatic product (bilirubin) or scaffold function mediates insulin signaling not resolved
    • No high-fat diet challenge to test metabolic stress
  9. 2020 Medium

    BVRA was linked to brain autophagy: global knockout caused AMPK dysregulation, mTOR hyperactivation, and impaired autophagy (reduced Beclin-1, LC3, Atg5-Atg12, Atg7) in cerebral cortex, establishing BVRA as a regulator of the AMPK/mTOR/autophagy axis in neurons.

    Evidence BVR-A knockout mouse, longitudinal cortex sampling at 2/6/11 months, immunoblotting for autophagy and mTOR/AMPK markers

    PMID:32727065

    Open questions at the time
    • Upstream mechanism by which BVRA regulates AMPK not defined
    • No rescue with bilirubin or catalytically dead BVRA mutant
  10. 2022 Medium

    In astrocytes, BVRA-generated bilirubin regulates mitochondrial function through an LKB1-SIRT1-ERRα axis independently of AMPKα, resolving that BVRA can engage distinct downstream pathways in different brain cell types.

    Evidence In vivo hippocampal BVR-A siRNA knockdown and astrocyte primary cultures with mitochondrial function assays and pathway immunoblotting

    PMID:36139815

    Open questions at the time
    • AMPK-independence not confirmed by genetic AMPK deletion
    • Stimulus (KRGE) is pharmacological, physiological trigger unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how the enzymatic versus non-enzymatic/scaffold functions of BVRA are distinguished in vivo using catalytically dead knock-in models; (2) the structural basis for BVRA's interaction with mTORC2 components and Nrf2; (3) whether BVRA's neuroprotective roles are primarily cell-autonomous or involve paracrine bilirubin signaling.
  • No catalytically dead knock-in model exists to separate enzymatic from scaffold functions
  • No high-resolution structure of BVRA-partner complexes
  • Cell-autonomous versus paracrine contributions not dissected in brain

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 GO:0016491 oxidoreductase activity 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
AKT1NFE2L2PRKAA1PRKCZTSC1TSC2

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 Human BLVRA encodes a monomeric enzyme that uses both NADH and NADPH as cofactors for biliverdin reductase activity, with both cofactor-dependent activities arising from a single gene product; chromosomally assigned to the p14→cen region of human chromosome 7. Gel electrophoresis with chromogenic staining, somatic cell hybrid panel Biochemical genetics Medium 6838484
1997 Rat BVR-A (ortholog of BLVRA) is a 34 kDa monomeric enzyme that catalyzes NADH oxidation exclusively via the B-face (pro-S hydride transfer) and exhibits pre-steady-state burst kinetics with pH dependence; the catalytic mechanism is intrinsic to the BVR-A domain and not affected by fusion to a GST dimerization domain. Recombinant GST-BVR-A expression, in vitro enzymatic assay, stereospecific [4-³H]NADH labeling, pre-steady-state kinetics The Biochemical journal High 9359830
2011 A homozygous nonsense mutation (p.Ser44X) in BLVRA generates a truncated protein with no catalytic activity, leading to accumulation of biliverdin IXα during cholestasis; demonstrated by site-directed mutagenesis of cloned human BLVRA, expression in hepatoma cells and Xenopus oocytes, and functional BVR activity assays. Site-directed mutagenesis, expression in human hepatoma cells and Xenopus oocytes, immunoblotting, immunofluorescence, functional enzymatic assay Journal of medical genetics High 21278388
2015 BVRA mediates macrophage expression of the anti-inflammatory cytokine IL-10: BVRA overexpression increases IL-10 levels and knockdown decreases them, without affecting TNF-α, placing BVRA specifically upstream of IL-10 in macrophage polarization signaling. Adenoviral overexpression and siRNA knockdown in bone marrow-derived macrophages; ELISA and mRNA quantification; in vivo renal ischemia-reperfusion injury model International journal of molecular sciences Medium 26393580
2018 miR-222 directly targets the 3′-UTR of BLVRA mRNA, repressing BLVRA protein levels and thereby inhibiting erythroid differentiation; overexpression of BLVRA rescues differentiation whereas BLVRA siRNA knockdown attenuates hemin-induced erythroid differentiation. Luciferase 3′-UTR reporter assay, miRNA mimic/inhibitor transfection, quantitative proteomics, siRNA knockdown, erythroid differentiation assay in K562 cells and CD34+ HPCs Cell biochemistry and function Medium 29368338
2019 TLR4/LPS activation suppresses BVRA expression in leukocytes, while biliverdin (BVRA substrate) inhibits TLR4 signaling and triggers phosphorylation of mTORC2-specific targets (Akt, PKCζ, AMPKα-LKB1-TSC1/2) that associate with BVRA; mTORC2 inhibitors (Torin, PP242) and a PKCζ inhibitory peptide block these BVRA-mediated responses, defining a BVRA/mTORC2 anti-inflammatory axis. Co-immunoprecipitation (association of AMPK/PKCζ/TSC1-2 with BVRA), phospho-protein immunoblotting, pharmacological inhibition (rapamycin, Torin, PP242, PKCζ peptide), in vivo cardiopulmonary bypass patient samples Scientific reports Medium 31065010
2019 CRISPR-Cas9 deletion of BVRA in murine hepatocytes reduces bilirubin production, leading to increased ROS, lipid accumulation, and reduced mitochondrial number/biogenesis markers, establishing BVRA's enzymatic activity as essential for hepatocyte antioxidant defense and lipid homeostasis. CRISPR-Cas9 knockout in hepa1c1c7 cells, mitochondrial oxygen consumption assay, lipid staining, ROS measurement, qRT-PCR of mitochondrial markers Archives of biochemistry and biophysics Medium 31422074
2020 Adipose-specific deletion of BVRA in mice reduces mitochondrial number in white adipose tissue (WAT), decreases browning genes (Ppara, Adrb3), increases adipocyte hypertrophy and inflammation, and impairs insulin signaling in WAT as evidenced by reduced phosphorylated AKT and Glut4 mRNA, demonstrating BVRA is required for WAT mitochondrial function and insulin signaling. Adipose-specific conditional Blvra knockout (BlvraFatKO) mouse model, body composition analysis, histology, mitochondria quantification, phospho-AKT immunoblotting, qRT-PCR Biomolecules Medium 32131495
2020 BVR-A deficiency in mouse cerebral cortex causes AMPK dysregulation, mTOR hyper-activation, and consequent impairment of autophagy (reduced Beclin-1, LC3, Atg5-Atg12 complex, Atg7), linking BVR-A to the AMPK/mTOR/autophagy axis in brain. BVR-A knock-out (BVR-A−/−) mouse model, longitudinal cortex sampling (2, 6, 11 months), immunoblotting for autophagy markers and mTOR/AMPK pathway components Antioxidants (Basel, Switzerland) Medium 32727065
2022 KRGE-induced BVR-A expression in hippocampal astrocytes increases bilirubin production, which regulates mitochondrial membrane potential, mass, and oxidative phosphorylation through an LKB1-SIRT1-ERRα axis (with SIRT5, Tom20/Tom22, cytochrome c, SOD2), independently of AMPKα, placing BVR-A upstream of LKB1-SIRT1 in astrocyte mitochondrial function. In vivo mouse hippocampus (BVR-A siRNA knockdown), astrocyte primary cultures, mitochondrial function assays, immunoblotting, immunofluorescence for Tom20/Tom22 Antioxidants (Basel, Switzerland) Medium 36139815
2023 A novel GK2-PTD fused BLVRA fusion protein transduces into dopaminergic neuronal cells and protects against MPP+-induced oxidative stress by suppressing MAPK activation and modulating apoptosis-related proteins (Bcl-2, Bax, cleaved caspase-3, -9), and reduces dopaminergic cell death in MPTP mouse model. Protein transduction domain fusion, SH-SY5Y cell protection assay, ROS measurement, MAPK/apoptosis immunoblotting, MPTP mouse model The FEBS journal Low 36688733
2026 BLVRA modulates neuroinflammatory cytokine production after subarachnoid hemorrhage via NOS2 and TLR4 signaling, independently of astrocyte polarization; combined DFX and siBLVRA treatment synergistically improved neurological outcomes, indicating BLVRA acts in an inflammatory signaling pathway downstream of TLR4. siBLVRA knockdown in mouse SAH model, neurological outcome scoring, NOS2/TLR4 immunoblotting, combined pharmacological/genetic intervention Experimental neurology Low 42031091
2025 BVRA directly interacts with Nrf2, the master redox transcription factor, in a non-enzymatic role; this BVRA-Nrf2 interaction coordinates expression of neuroprotective genes (revealed by ChIP-seq and RNA-seq) that are dysregulated in Alzheimer's disease, establishing BVRA as a dual-function antioxidant integrator bridging lipophilic (bilirubin) and hydrophilic (Nrf2 transcriptional) defense mechanisms. Co-immunoprecipitation (BVRA-Nrf2 interaction), ChIP-seq, RNA-seq in BVR-A knockout vs. wild-type neurons bioRxivpreprint Medium bio_10.1101_2025.06.04.657936

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 A homozygous nonsense mutation (c.214C->A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis. Journal of medical genetics 47 21278388
2020 Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice. Biomolecules 45 32131495
2019 CRISPR Cas9-mediated deletion of biliverdin reductase A (BVRA) in mouse liver cells induces oxidative stress and lipid accumulation. Archives of biochemistry and biophysics 35 31422074
2020 Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1. Antioxidants (Basel, Switzerland) 30 32961782
2015 Biliverdin Reductase A (BVRA) Mediates Macrophage Expression of Interleukin-10 in Injured Kidney. International journal of molecular sciences 20 26393580
2020 BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain-Implications for Neurodegeneration. Antioxidants (Basel, Switzerland) 18 32727065
1983 Electrophoretic characterization and genetics of human biliverdin reductase (BLVR; EC 1.3.1.24); assignment of BLVR to the p14 leads to cen region of human chromosome 7 in mouse-human somatic cell hybrids. Biochemical genetics 16 6838484
2019 TLR4 counteracts BVRA signaling in human leukocytes via differential regulation of AMPK, mTORC1 and mTORC2. Scientific reports 14 31065010
1989 Localization of Blvr, biliverdin reductase, on mouse chromosome 2. Genomics 13 2793182
2016 Predictive role BLVRA mRNA expression in hepatocellular cancer. Annals of hepatology 12 27740521
1997 Cloning and overexpression of rat kidney biliverdin IX alpha reductase as a fusion protein with glutathione S-transferase: stereochemistry of NADH oxidation and evidence that the presence of the glutathione S-transferase domain does not effect BVR-A activity. The Biochemical journal 11 9359830
2011 Association of a BLVRA common polymorphism with essential hypertension and blood pressure in Kazaks. Clinical and experimental hypertension (New York, N.Y. : 1993) 10 21721974
2019 Associations between G6PD, OATP1B1 and BLVRA variants and susceptibility to neonatal hyperbilirubinaemia in a Chinese Han population. Journal of paediatrics and child health 9 30636082
2018 Quantitative proteomics reveals that miR-222 inhibits erythroid differentiation by targeting BLVRA and CRKL. Cell biochemistry and function 8 29368338
2022 Induction of BVR-A Expression by Korean Red Ginseng in Murine Hippocampal Astrocytes: Role of Bilirubin in Mitochondrial Function via the LKB1-SIRT1-ERRα Axis. Antioxidants (Basel, Switzerland) 7 36139815
2020 Biliverdin Reductase A (BLVRA) Promotes Colorectal Cancer Cell Progression by Activating the Wnt/β-Catenin Signaling Pathway. Cancer management and research 7 32425592
2023 Dynamic Changes of BVRA Protein Levels Occur in Response to Insulin: A Pilot Study in Humans. International journal of molecular sciences 5 37108445
2024 Associations between UGT1A1, SLCO1B1, SLCO1B3, BLVRA and HMOX1 polymorphisms and susceptibility to neonatal severe hyperbilirubinemia in Chinese Han population. BMC pediatrics 4 38279097
1991 Mapping of silver fox genes: chromosomal localization of the genes for GOT2, AK1, ALDOC, ACP1, ITPA, PGP, and BLVR. Cytogenetics and cell genetics 2 1647290
2024 BLVRA exerts its biological effects to induce malignant properties of hepatocellular carcinoma cells via Wnt/β-catenin pathway. Journal of molecular histology 1 38216836
2024 UGT1A1 and BLVRA allele and genotype variants in neonatal patients with hyperbilirubinemia in southern China. Scientific reports 1 39468242
2023 Protective effect of GK2 fused BLVRA protein against oxidative stress-induced dopaminergic neuronal cell damage. The FEBS journal 1 36688733
1990 [Mapping of the silver fox genome. III. Determination of the chromosomal localization of the GOT2, AK1, ALDOC, ACP1, ITPA, PGP and BLVR genes]. Genetika 1 2074010
2026 Multiomics analysis reveals that chlorogenic acid alleviates heat stress-induced oxidative damage in prepubertal boar testes via the BLVRA-GPX3 pathway: in vivo and in vitro evidence. Journal of animal science and biotechnology 0 41530826
2026 Understanding exacerbation risk in BLVR: A logistic regression approach to complication prediction. Chronic respiratory disease 0 42018974
2026 Combined targeting of iron overload and BLVRA synergistically attenuates reactive astrocytes after subarachnoid hemorrhage. Experimental neurology 0 42031091
2025 BLVRA promotes glioblastoma progression by regulating fatty acid metabolism. Scientific reports 0 41023045
2024 Biliverdinuria Caused by Exonic BLVRA Deletions in Two Dogs with Green Urine. Genes 0 39766828