Affinage

BLVRA

Biliverdin reductase A · UniProt P53004

Length
296 aa
Mass
33.4 kDa
Annotated
2026-06-09
28 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BLVRA encodes biliverdin reductase A, a monomeric ~34 kDa cytosolic enzyme that catalyzes the B-face stereospecific reduction of biliverdin IXα to bilirubin using either NADH or NADPH, with both cofactor activities arising from a single gene product (PMID:6838484, PMID:9359830). Complete loss of catalytic activity through nonsense or large deletion mutations causes biliverdin accumulation (hyperbiliverdinaemia/biliverdinuria) and is non-lethal in both humans and dogs (PMID:21278388, PMID:39766828). Beyond bilirubin synthesis, BVRA serves as a signaling node that physically associates with mTORC2-pathway components (Akt, PKCζ, the AMPKα–LKB1–TSC1/2 module) to restrain TLR4-driven inflammation in leukocytes, a reciprocally regulated axis in which TLR4 activation suppresses BVRA (PMID:31065010), and it specifically promotes anti-inflammatory IL-10 expression in macrophages (PMID:26393580). Through its bilirubin-generating and signaling functions BVRA protects cells from oxidative stress and supports mitochondrial biogenesis and oxidative phosphorylation in hepatocytes and adipocytes, where its loss produces lipid accumulation, mitochondrial deficits, and impaired insulin signaling (PMID:31422074, PMID:32131495). In brain, BVRA constrains mTOR activity and sustains autophagy via AMPK, and protects neurons against oxidative damage (PMID:32727065, PMID:36688733). BVRA also acts on cell-fate programs, being required for hemin-induced erythroid differentiation downstream of miR-222 regulation (PMID:29368338).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1983 Medium

    Established that a single BLVRA gene product is a monomeric enzyme able to use both NADH and NADPH, resolving whether the dual-cofactor activity reflected one or two enzymes.

    Evidence Gel electrophoresis with chromogenic staining and somatic cell hybrid mapping

    PMID:6838484

    Open questions at the time
    • Catalytic mechanism and stereochemistry not addressed
    • No recombinant reconstitution
  2. 1997 High

    Defined the enzymatic mechanism, showing BVR-A reduces biliverdin IXα to bilirubin with B-face stereospecific oxidation of NADH, establishing the chemistry of the core reaction.

    Evidence Recombinant GST-BVR-A, gel filtration, in vitro assay, [4-³H]NADH stereospecificity, pre-steady-state burst kinetics

    PMID:9359830

    Open questions at the time
    • Structural basis of stereospecificity not resolved
    • Physiological consequences of bilirubin production not addressed
  3. 2011 High

    Demonstrated that complete loss of BVR-A activity in humans causes biliverdin accumulation but is non-lethal, defining the in vivo consequence of enzyme failure.

    Evidence Site-directed mutagenesis of c.214C>A (p.Ser44X), heterologous expression in hepatoma cells and Xenopus oocytes, activity assay, human patients

    PMID:21278388

    Open questions at the time
    • Why loss is tolerated despite proposed signaling roles is unexplained
    • Non-enzymatic functions not tested in patients
  4. 2015 Medium

    Showed BVRA selectively drives macrophage IL-10 expression without affecting TNF-α, identifying a specific anti-inflammatory regulatory role.

    Evidence Adenoviral overexpression and siRNA knockdown in BMDMs, ELISA/mRNA, in vivo renal ischemia-reperfusion

    PMID:26393580

    Open questions at the time
    • Molecular link between BVRA and IL-10 transcription not defined
    • Single lab
  5. 2018 Medium

    Placed BLVRA in a post-transcriptional regulatory circuit (miR-222 target) and showed it is required for erythroid differentiation, connecting the enzyme to cell-fate control.

    Evidence 3'-UTR luciferase reporter, miR-222 mimic/inhibitor, siRNA, quantitative proteomics, erythroid differentiation of K562 and CD34+ cells

    PMID:29368338

    Open questions at the time
    • Whether the differentiation effect requires enzymatic activity unknown
    • Downstream effectors not identified
  6. 2019 Medium

    Defined BVRA as a signaling scaffold that physically engages mTORC2 targets (Akt, PKCζ, AMPKα-LKB1-TSC1/2) to suppress TLR4 inflammation, revealing a non-canonical, reciprocally regulated function.

    Evidence Phosphoprotein Western blot, Co-IP of BVRA with mTORC2 targets, pharmacological inhibition (Torin, PP242, PKCζ peptide), human bypass and T2D samples

    PMID:31065010

    Open questions at the time
    • Direct binding interfaces not mapped
    • Single lab without reciprocal structural validation
  7. 2019 Medium

    Established BVRA as a protector against hepatocyte lipid accumulation and oxidative stress through support of mitochondrial biogenesis and respiration.

    Evidence CRISPR-Cas9 knockout in hepa1c1c7 cells, activity assay, lipid/ROS staining, mitochondrial respiration, gene expression

    PMID:31422074

    Open questions at the time
    • Enzymatic vs scaffold contribution to mitochondrial phenotype not separated
    • Single cell model
  8. 2020 Medium

    Extended BVRA's metabolic role to adipose tissue, showing adipose-specific deletion impairs WAT mitochondrial function and insulin signaling and promotes adiposity and inflammation.

    Evidence Adipose-specific Blvra knockout mice, body composition, histology, expression profiling, pAKT Western blot

    PMID:32131495

    Open questions at the time
    • Upstream mechanism linking BVRA to browning genes not defined
    • Single lab
  9. 2020 Medium

    Showed BVR-A deficiency in brain cortex hyperactivates mTOR and impairs autophagy with dysregulated AMPK as the upstream driver, defining a neural AMPK/mTOR/autophagy role.

    Evidence BVR-A knockout mice, longitudinal cortex analysis, Western blot for mTOR/AMPK/autophagy markers

    PMID:32727065

    Open questions at the time
    • How BVRA controls AMPK mechanistically unresolved
    • Behavioral/cognitive outcomes not linked
  10. 2020 Low

    Linked BLVRA to Wnt/β-catenin signaling and proliferation in colorectal cancer cells via gain/loss-of-function.

    Evidence Lentiviral overexpression/knockdown in HT-29 and SW620, Western blot, proliferation/migration/invasion assays

    PMID:32425592

    Open questions at the time
    • No direct biochemical link between BLVRA and Wnt components established
    • Single study, single lab
  11. 2020 Low

    Correlated exercise-associated hepatic BVRA upregulation with elevated bilirubin and PPARα target genes in a selected rat model.

    Evidence HCR vs LCR rat strains, plasma bilirubin, hepatic enzyme quantification, gene expression

    PMID:32961782

    Open questions at the time
    • Correlative only, no direct intervention on BVRA
    • Causality unestablished
  12. 2022 Low

    Placed BVR-A in an AMPKα-independent LKB1-SIRT1-ERRα axis controlling astrocyte mitochondrial function via bilirubin production.

    Evidence KRGE treatment of astrocytes in vivo/in vitro, BVR-A KD/OE, mitochondrial membrane potential, Western blot, immunofluorescence

    PMID:36139815

    Open questions at the time
    • Mechanism is indirect via bilirubin
    • Single study, single lab
  13. 2023 Medium

    Demonstrated that delivered BLVRA antioxidant activity protects dopaminergic neurons by suppressing MAPK and apoptotic signaling in PD models.

    Evidence GK2-BLVRA fusion protein transduction into SH-SY5Y and MPTP mice, Western blot, ROS, immunohistochemistry

    PMID:36688733

    Open questions at the time
    • Whether endogenous BVRA confers the same protection not tested
    • Distinction between enzymatic and scaffold contribution unclear
  14. 2024 Medium

    Confirmed in a second mammal (dog) that BLVRA loss-of-function causes biliverdin accumulation, generalizing the human enzymatic-deficiency phenotype.

    Evidence Whole genome and Sanger sequencing, urinary mass spectrometry for biliverdin in dogs

    PMID:39766828

    Open questions at the time
    • Non-enzymatic functions not assessed in this ortholog
    • Systemic consequences not characterized
  15. 2024 Low

    Reinforced BLVRA's upstream role in Wnt/β-catenin signaling in hepatocellular carcinoma using pharmacological epistasis.

    Evidence siRNA knockdown in HepG2/Hep3B, Western blot, proliferation/apoptosis assays, Wnt inhibitor IWP-4 epistasis

    PMID:38216836

    Open questions at the time
    • No direct biochemical interaction with Wnt components shown
    • Single lab
  16. 2025 Medium

    Proposed a non-enzymatic role for BVRA as a direct Nrf2 partner shaping neuroprotective transcriptional output, expanding its function into redox gene regulation.

    Evidence Co-IP/interaction assay, ChIP-seq, RNA-seq in brain cells with BVRA knockout comparison (preprint)

    PMID:bio_10.1101_2025.06.04.657936

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Direct binding interface and mechanism of transcriptional modulation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how BVRA's enzymatic (bilirubin-producing) and non-enzymatic (scaffold/transcriptional) functions are mechanistically partitioned and which underlies each tissue-specific phenotype.
  • No structural model distinguishing catalytic vs interaction surfaces
  • Causal separation of enzyme vs scaffold roles not achieved across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0016209 antioxidant activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2
Partners
AKT1NFE2L2PRKAA1PRKCZSTK11

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 BLVRA encodes a monomeric enzyme (~34 kDa) that uses both NADH and NADPH as cofactors, with both activities arising from a single gene product. Demonstrated by gel electrophoresis with chromogenic staining and somatic cell hybrid mapping. Gel electrophoresis with specific chromogenic staining; somatic cell hybrid complementation Biochemical genetics Medium 6838484
1997 BVR-A catalyzes reduction of biliverdin IXα to bilirubin as a monomer (~34 kDa) using NADH; the reaction proceeds with B-face stereospecific oxidation of NADH, demonstrated by pre-steady-state burst kinetics with pH dependence. Recombinant GST-BVR-A fusion protein expression, gel filtration, in vitro enzymatic assay, stereospecificity assay with [4-³H]NADH The Biochemical journal High 9359830
2011 A homozygous nonsense mutation (c.214C>A, p.Ser44X) in BLVRA generates a truncated protein with no catalytic activity, leading to accumulation of biliverdin (hyperbiliverdinaemia) during cholestasis episodes. Complete absence of BVR-A activity is non-lethal. Site-directed mutagenesis, expression in human hepatoma liver cells and Xenopus laevis oocytes, immunoblotting, immunofluorescence, functional BVR-A activity assay Journal of medical genetics High 21278388
2015 BVRA mediates macrophage expression of the anti-inflammatory cytokine IL-10. BVRA overexpression increased IL-10 mRNA and protein levels, while BVRA knockdown decreased IL-10, without affecting TNF-α, indicating a specific IL-10 regulatory role in macrophages. Recombinant adenovirus-mediated BVRA 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 BLVRA is a direct target of miR-222 at its 3'-UTR; miR-222 suppression increases BLVRA protein levels, and BLVRA overexpression promotes erythroid differentiation of K562 cells and CD34+ HPCs, while BLVRA silencing attenuates hemin-induced erythroid differentiation. Luciferase 3'-UTR reporter assay, miR-222 mimic/inhibitor transfection, siRNA knockdown, quantitative proteomics, erythroid differentiation assay Cell biochemistry and function Medium 29368338
2019 BVRA-mediated biliverdin reduction to bilirubin inhibits TLR4 signaling in human leukocytes. Biliverdin triggers phosphorylation of mTORC2-specific targets (Akt, PKCζ, AMPKα-LKB1-TSC1/2) and their physical association with BVRA. TLR4 activation counter-suppresses BVRA expression, indicating a reciprocal regulatory axis. Phosphoprotein analysis (Western blot), co-immunoprecipitation of BVRA with mTORC2 targets, pharmacological inhibition (Torin, PP242, PKCζ inhibitory peptide), in vivo human samples (cardiopulmonary bypass patients, T2D patients) Scientific reports Medium 31065010
2019 Loss of BVRA in hepatocytes (CRISPR-Cas9 knockout) causes reduced bilirubin production, increased ROS, lipid accumulation, decreased mitochondrial number, reduced mitochondrial biogenesis markers, and impaired oxidative phosphorylation, establishing BVRA as a protector against lipid accumulation and oxidative stress in hepatocytes. CRISPR-Cas9 gene knockout in murine hepa1c1c7 hepatocytes, enzymatic activity assay, lipid staining, ROS measurement, mitochondrial oxygen consumption assay, gene expression analysis Archives of biochemistry and biophysics Medium 31422074
2020 Adipose-specific deletion of BVRA in mice leads to increased visceral fat, reduced mitochondrial number in white adipose tissue (WAT), increased adipocyte hypertrophy and inflammation, decreased expression of browning genes (Ppara, Adrb3), and impaired insulin signaling in WAT (reduced pAKT and Glut4 mRNA), establishing BVRA as a regulator of WAT mitochondrial function and insulin signaling. Adipose-specific conditional Blvra knockout mouse (BlvraFatKO), body composition analysis, histology, gene expression profiling, Western blot for pAKT Biomolecules Medium 32131495
2020 BVR-A deficiency in mouse brain cortex leads to mTOR hyperactivation and impairment of autophagy (reduced Beclin-1, LC3, LC3II/I ratio, Atg5-Atg12, Atg7), with dysregulated AMPK identified as the critical upstream driver of mTOR hyperactivation in the absence of BVR-A. BVR-A knockout mouse (BVR-A-/-), age-series cortex analysis (2, 6, 11 months), Western blot for mTOR/AMPK/autophagy pathway components, oxidative stress markers Antioxidants (Basel, Switzerland) Medium 32727065
2020 BLVRA overexpression in colorectal cancer cells activates Wnt/β-catenin signaling (upregulates c-MYC, β-catenin, Cyclin D1) to promote proliferation, migration, invasion, and EMT; BLVRA knockdown produces opposite effects and blocks pathway activation. Lentiviral overexpression and knockdown in HT-29 and SW620 CRC cells, Western blot for Wnt/β-catenin pathway targets, MTT proliferation assay, flow cytometry apoptosis, Transwell migration/invasion assay Cancer management and research Low 32425592
2020 Elevated BVRA in high-capacity running (HCR) rats correlates with higher plasma bilirubin and reduced UGT1A1, and increased PPARα target genes (Fgf21, Abcd3, Gys2), indicating that exercise-induced increases in bilirubin production involve upregulation of hepatic BVRA and suppression of UGT1A1. Genetically selected rat strains (HCR vs LCR), plasma bilirubin measurement, hepatic enzyme protein/activity quantification, gene expression analysis, PAS staining for glycogen Antioxidants (Basel, Switzerland) Low 32961782
2022 KRGE-induced BVR-A expression and subsequent bilirubin production in astrocytes regulates mitochondrial function (membrane potential, mass, oxidative phosphorylation) through LKB1, SIRT1, and ERRα, and modulates mitochondria-localized proteins (SIRT5, Tom20, Tom22, cytochrome c, SOD2). This BVR-A-LKB1-SIRT1-ERRα pathway was AMPKα-independent. KRGE treatment of hippocampal astrocytes in vivo (mice) and in vitro, BVR-A knockdown/overexpression, mitochondrial membrane potential assay, Western blot for pathway components, immunofluorescence Antioxidants (Basel, Switzerland) Low 36139815
2023 GK2-BLVRA fusion protein (using a novel protein transduction domain) transduces into dopaminergic neurons, suppresses MAPK activation, modulates apoptosis-related proteins (Bcl-2, Bax, caspase-3/-9), reduces ROS and DNA damage after MPP+ exposure, and reduces dopaminergic neuronal death in MPTP-treated mice, demonstrating that BLVRA antioxidant activity protects dopaminergic neurons. Recombinant fusion protein transduction into SH-SY5Y cells and in vivo MPTP mouse model; Western blot for MAPK and apoptosis proteins; ROS measurement; immunohistochemistry for dopaminergic neurons The FEBS journal Medium 36688733
2024 BLVRA knockdown in HCC cells (HepG2, Hep3B) suppresses proliferation, cell cycle progression, invasion, migration, and induces apoptosis, with reduction of Wnt/β-catenin targets (c-MYC, β-catenin, Cyclin D1); WNT inhibitor IWP-4 phenocopies BLVRA knockdown, placing BLVRA upstream of Wnt/β-catenin in HCC. siRNA knockdown in HCC cell lines, Western blot for Wnt/β-catenin pathway, cell proliferation and apoptosis assays, pharmacological Wnt inhibition (IWP-4), invasion/migration assays Journal of molecular histology Low 38216836
2024 Homozygous large deletions in canine BLVRA causing predicted truncations result in loss of BVR-A enzymatic function and biliverdinuria, confirming that BLVRA loss-of-function causes biliverdin accumulation in a non-human mammal. Whole genome sequencing, Sanger sequencing, urinary mass spectrometry for biliverdin quantification in dogs Genes Medium 39766828
2025 BVRA directly interacts with Nrf2 (the master redox transcription factor) in a non-enzymatic capacity, modulating the expression of neuroprotective Nrf2 target genes including those dysregulated in Alzheimer's disease, as revealed by ChIP-seq and RNA-seq. Co-immunoprecipitation/direct interaction assay, ChIP-seq, RNA-seq in brain cells; BVRA knockout model comparison 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 46 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 37 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
2020 Biliverdin Reductase A (BLVRA) Promotes Colorectal Cancer Cell Progression by Activating the Wnt/β-Catenin Signaling Pathway. Cancer management and research 8 32425592
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
2024 Associations between UGT1A1, SLCO1B1, SLCO1B3, BLVRA and HMOX1 polymorphisms and susceptibility to neonatal severe hyperbilirubinemia in Chinese Han population. BMC pediatrics 5 38279097
2023 Dynamic Changes of BVRA Protein Levels Occur in Response to Insulin: A Pilot Study in Humans. International journal of molecular sciences 5 37108445
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

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