Affinage

LRAT

Lecithin retinol acyltransferase · UniProt O95237

Length
230 aa
Mass
25.7 kDa
Annotated
2026-06-10
38 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRAT is the predominant enzyme catalyzing physiologic esterification of retinol into retinyl esters, the principal storage form of vitamin A, with Lrat-null mice retaining only trace retinyl esters across liver, lung, kidney, and retinal pigment epithelium (PMID:16115871). It is an NlpC/P60-family acyltransferase that acts through a thioester catalytic intermediate; structural analysis of an HRASLS3-LRAT chimera showed that the LRAT-specific domain drives domain-swapping dimerization and slows hydrolysis of the intermediate, thereby favoring efficient acyl transfer onto retinol and conferring LRAT's substrate specificity within its protein family (PMID:25383759). The enzyme is restricted to ER-enriched membranes, establishing the ER as the site of retinol esterification, including within the visual cycle of the RPE (PMID:17504753, PMID:9767084). In the eye, RPE-specific ablation of LRAT depletes retinyl ester stores and impairs light responses, demonstrating that LRAT supplies the retinyl ester substrate that feeds the visual cycle (PMID:18055784), and an N-terminal LCA-associated E14L mutation destabilizes the protein and elevates cellular retinoic acid upon retinoid supplementation, implicating retinoid dysregulation in the associated retinal pathology (PMID:28758396). Beyond storage, LRAT shapes retinoid signaling and homeostasis: by maintaining an inward retinol gradient it enables STRA6/JAK2/STAT5 signaling driven by holo-RBP (PMID:24036882), and in the intestine its retinyl ester sequestration sets a negative-feedback loop in which loss of LRAT renders the ISX transcription factor hypersensitive to vitamin A and suppresses BCO1-dependent beta-carotene conversion (PMID:33631212). In hepatic stellate cells LRAT is the dominant retinyl ester synthase of the quiescent state and is required for the large characteristic lipid droplets; upon activation cells shift retinyl ester synthesis to DGAT1 (PMID:27815220, PMID:39068984). LRAT transcription is itself induced by retinoic acid through RAR/RXR acting on a conserved proximal promoter that lacks canonical response elements (PMID:19665987).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 Medium

    Localizing LRAT activity established where retinol esterification physically occurs, answering whether the visual-cycle esterification step is an ER event.

    Evidence subcellular membrane fractionation with marker enzymes and LRAT activity assays in bovine RPE

    PMID:9767084

    Open questions at the time
    • Single method in one tissue
    • Does not identify the membrane-targeting determinant of LRAT
  2. 2001 Medium

    Identifying that LRAT induction during hepatic stellate cell conversion is retinoic-acid dependent distinguished it from the fat-storage-driven ARAT pathway and linked LRAT to retinoid-responsive lipocyte biology.

    Evidence [3H]retinol labeling and microsomal kinetic assays in GRX cells and primary murine HSCs with retinoic acid treatment

    PMID:12031254

    Open questions at the time
    • Does not resolve the transcriptional mechanism of induction
    • Relative in vivo contributions of LRAT vs ARAT not quantified
  3. 2005 High

    Genetic knockout defined LRAT as the dominant physiologic retinyl ester synthase across multiple tissues and revealed a compensatory acyl-CoA-dependent ARAT pathway, answering which enzyme governs vitamin A storage.

    Evidence Lrat-/- mice with HPLC retinoid quantification, hepatic stellate cell EM, and chylomicron fractionation

    PMID:16115871

    Open questions at the time
    • Molecular identity of the compensatory ARAT enzyme not established
    • Tissue-specific contributions not separated
  4. 2005 Low

    A homologous internal region of LRAT was reported to carry anti-proliferative and DNA-binding activity, raising a possible non-esterase function.

    Evidence synthetic dodecapeptide growth-inhibition assays, nude-mouse tumor model, and nuclear localization imaging

    PMID:16234259

    Open questions at the time
    • Uses peptides rather than full-length LRAT protein
    • No demonstration that endogenous LRAT exerts this activity
    • Mechanism of CDK2/cyclin effects indirect
  5. 2007 High

    Compartmentalizing LRAT to the ER versus retinyl ester hydrolase to the plasma membrane, and showing RPE65 is not palmitoylated by LRAT, clarified LRAT's strictly substrate-supplying role in the visual cycle.

    Evidence lrat-/- RPE fractionation, mass spectrometry of RPE65 cysteines, 2-bromopalmitate inhibition, and isomerase assays

    PMID:17504753

    Open questions at the time
    • Does not address LRAT regulation within the RPE
    • ER-targeting determinants unresolved
  6. 2007 High

    RPE-specific ablation demonstrated that LRAT activity in the RPE is functionally required for vision, not merely for storage, by linking it to electroretinographic light responses.

    Evidence Tyrp1-Cre x Lrat-flox tissue-specific knockout with HPLC retinoids and electroretinography

    PMID:18055784

    Open questions at the time
    • Does not quantify the degree of photoreceptor degeneration over time
    • Extra-RPE contributions to phenotype not isolated
  7. 2009 Medium

    Mapping the Lrat promoter explained how retinoic acid induces LRAT despite the absence of canonical retinoid response elements, identifying an essential conserved proximal region.

    Evidence nuclear run-on, luciferase reporter deletion constructs, nuclear receptor co-transfection, and EMSA

    PMID:19665987

    Open questions at the time
    • Direct DNA-binding factor at the responsive element not definitively identified
    • Indirect vs direct RAR/RXR action not fully resolved
  8. 2013 High

    Linking LRAT to STRA6 signaling established that retinol esterification, by maintaining an inward retinol gradient, is required to drive holo-RBP-induced JAK2/STAT5 signaling and its metabolic consequences.

    Evidence LRAT-null mice, cell-based JAK2/STAT5 assays, insulin signaling readouts, and genetic epistasis

    PMID:24036882

    Open questions at the time
    • Does not define cell types in vivo where this axis dominates
    • Quantitative gradient parameters not measured
  9. 2016 Medium

    Quantitative lipidomics in knockout HSCs assigned LRAT responsibility for the large lipid droplets of quiescent cells and revealed a synthesis handoff to DGAT1 upon activation.

    Evidence Lrat-/- primary HSCs with LC-MS/MS retinyl ester profiling and lipid droplet size imaging

    PMID:27815220

    Open questions at the time
    • Mechanism linking LRAT activity to droplet size not defined
    • In vivo relevance of the DGAT1 switch not tested
  10. 2021 High

    Genetic and pharmacological epistasis showed that LRAT-mediated retinyl ester sequestration sets the sensitivity of the ISX/BCO1 feedback loop controlling intestinal beta-carotene conversion.

    Evidence Lrat-/-, Isx-/- and retinoid-inhibitor mouse models with tissue retinoid/carotenoid quantification

    PMID:33631212

    Open questions at the time
    • Does not establish whether LRAT acts cell-autonomously in enterocytes
    • Kinetics of feedback not characterized
  11. 2024 Medium

    Time-resolved analysis of HSC activation showed that early retinyl ester loss is driven by enhanced ester breakdown while LRAT synthesis persists, refining the timing of the LRAT-to-DGAT1 switch.

    Evidence soft-gel vs plastic primary HSC culture with LC-MS/MS, LRAT activity assays, and expression profiling

    PMID:39068984

    Open questions at the time
    • Identity of the breakdown hydrolase not established
    • In vivo fibrosis relevance not tested
  12. 2038 Low

    Imaging-based work proposed LRAT as an organizer of DHRS3 at ER-LD-mitochondria contacts coupling retinoid metabolism to NADPH/redox buffering.

    Evidence spatial co-localization imaging, LRAT knockdown, enforced mitochondrial DHRS3 targeting, and NADP+/NADPH and ROS measurements

    PMID:41579973

    Open questions at the time
    • Single lab, not independently replicated
    • Direct LRAT-DHRS3 interaction not demonstrated
    • Rescue only partial

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular determinants of LRAT ER membrane targeting and the identity of the compensatory ARAT and retinyl-ester hydrolase enzymes that act alongside LRAT remain unresolved.
  • No structure of full-length membrane-embedded LRAT
  • Compensatory ARAT enzyme unidentified
  • Hydrolase mediating activation-induced retinyl ester loss unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005811 lipid droplet 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 1 R-HSA-9709957 Sensory Perception 1
Partners
DHRS3

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 A 2.2-Å crystal structure of an HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed that the LRAT-specific domain causes domain-swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer to retinol substrate. This identified the structural basis for LRAT's substrate specificity within the NlpC/P60 protein family. Gain-of-function domain-swap chimera, 2.2-Å crystal structure of thioester intermediate, in vitro enzymatic assay Nature chemical biology High 25383759
2005 LRAT is the predominant enzyme responsible for physiologic retinol esterification in liver, lung, kidney, and retinal pigment epithelium. Lrat-/- mice have only trace retinyl esters in these tissues and absorb dietary retinol primarily as free retinol in chylomicrons. The fatty acyl composition of residual chylomicron retinyl esters in Lrat-/- mice suggests synthesis via an acyl-CoA-dependent acyltransferase (ARAT) pathway in adipose tissue, which also shows elevated CRBPIII expression and compensatory retinyl ester storage. Lrat knockout mouse (Lrat-/-), HPLC retinoid quantification, electron microscopy of hepatic stellate cells, chylomicron fractionation, fatty acyl composition analysis The Journal of biological chemistry High 16115871
2007 LRAT activity is localized exclusively to endoplasmic reticulum (ER)-enriched membranes in bovine RPE, whereas 11-cis retinyl ester hydrolase (REH) activity is in plasma membrane fractions, indicating subcellular compartmentalization of the visual cycle. LRAT is not required for RPE65's association with membranes or for RPE65 isomerase activity beyond its role in synthesizing the retinyl ester substrate; Rpe65 membrane affinity is similar in wild-type and lrat-/- mice, and mass spectrometry showed that Cys231, Cys329, and Cys330 of RPE65 are not palmitoylated by LRAT. Subcellular membrane fractionation with enzyme marker assays, lrat-/- mouse RPE homogenates, mass spectrometry for palmitoylation, 2-bromopalmitate inhibition, isomerase activity assays with retinyl palmitate vs. retinol substrates The Journal of biological chemistry High 17504753
2007 RPE-specific somatic ablation of Lrat in mice (Lrat-rpe-/-) strongly reduced retinyl ester synthesis in RPE cells and resulted in reduced light responses in ERG recordings, demonstrating that LRAT activity in the RPE is required for normal visual cycle function and retinoid storage. Cre-loxP tissue-specific knockout (Tyrp1-Cre × Lrat-flox), RNA/protein expression analysis, HPLC retinoid quantification, electroretinography Investigative ophthalmology & visual science High 18055784
2013 LRAT-catalyzed retinol esterification is required for activation of the STRA6/JAK2/STAT5 signaling cascade by holo-RBP. LRAT-null mice are protected from holo-RBP-induced suppression of insulin signaling, demonstrating that LRAT supports STRA6-mediated cell signaling by maintaining an inward retinol concentration gradient that enables STRA6-mediated retinol transport. LRAT-null mice, cell-based signaling assays (JAK2/STAT5 activation), insulin signaling readouts, genetic epistasis FASEB journal High 24036882
2021 LRAT's catalytic activity (retinyl ester sequestration) is central to the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene. In LRAT-deficient mice, the transcription factor ISX becomes hypersensitive to dietary vitamin A and suppresses β-carotene oxygenase-1 (BCO1), resulting in β-carotene accumulation and vitamin A deficiency in extrahepatic tissues. Pharmacological inhibition of retinoid signaling and genetic depletion of Isx restored biosynthesis in enterocytes. Lrat-/- mice, pharmacological retinoid signaling inhibition, Isx-/- genetic epistasis, retinoid/carotenoid quantification in tissues Journal of lipid research High 33631212
2017 The LCA-associated E14L LRAT mutation causes instability and accelerated proteasomal degradation of the mutant protein. Despite reduced protein stability, LRAT(E14L) expression led to rapid increase in cellular retinoic acid levels upon retinoid supplementation rather than abrogating chromophore production, implicating elevated retinoic acid in the retinal pathology caused by this N-terminal mutation. Bicistronic LRAT(E14L)-EGFP expression system, cell-based retinoid metabolite analysis, proteasomal degradation assays, chromophore production assay Biochemistry Medium 28758396
1998 In bovine RPE subcellular membrane fractions, LRAT activity is restricted to ER-enriched membranes, establishing the ER as the subcellular site of retinol esterification in the visual cycle. Subcellular membrane fractionation with ER and plasma membrane marker enzymes, LRAT activity assay Biochimica et biophysica acta Medium 9767084
2009 The Lrat gene promoter lacks canonical retinoid receptor binding elements, yet its transcription is regulated by retinoic acid and nuclear receptors (RARα, RARβ, RARγ with RXRα) acting through an essential proximal region (~300 bp upstream of TSS) containing conserved basal elements (TATA box, SP3, AP-1, CAAT box). Nuclear run-on assays confirmed transcriptional regulation in vivo; removal of the −111 bp region completely eliminated promoter activity. Nuclear run-on transcription assay, luciferase reporter with deletion constructs, nuclear receptor co-transfection, electrophoretic mobility shift assay Archives of biochemistry and biophysics Medium 19665987
2001 Both LRAT and ARAT activities are induced during conversion of hepatic stellate cell myofibroblasts to lipocytes. LRAT induction was dependent on retinoic acid, whereas ARAT induction depended on the overall fat-storing phenotype. Microsomal enzyme kinetics confirmed that these are intrinsic activities not solely attributable to changes in retinol uptake. [3H]retinol metabolic labeling, microsomal fraction kinetic enzyme assays, retinoic acid treatment, GRX cell line and primary murine HSCs The Journal of nutritional biochemistry Medium 12031254
2016 Quiescent LRAT-/- hepatic stellate cells retain the capacity to synthesize retinyl esters and store neutral lipids in lipid droplets ex vivo, but lipid droplet size is significantly smaller (median 1080 nm vs. 1618 nm in WT). During activation, HSCs shift retinyl ester synthesis from LRAT to DGAT1, and exogenous fatty acid composition becomes the major determinant of retinyl ester species, indicating that LRAT is responsible for the large lipid droplets characteristic of quiescent HSCs. Lrat-/- primary HSCs, LC-MS/MS with multiple reaction monitoring for retinyl ester species, lipid droplet size quantification by microscopy, comparison with DGAT1-expressing activated cells Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 27815220
2024 During early hepatic stellate cell activation, LRAT activity is maintained and continues to produce retinyl palmitate-enriched retinyl esters, while loss of retinyl ester stores is caused by enhanced retinyl ester breakdown rather than loss of LRAT synthesis activity. Only upon prolonged activation do HSCs lose LRAT activity and shift to DGAT1-mediated retinyl ester synthesis. Soft gel vs. plastic culture comparison of primary HSCs, LC-MS/MS retinyl ester quantification, LRAT activity assays, gene expression analysis Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 39068984
2005 A sequence-homologous region (AA 111–123) within LRAT (and the related LRAT-like proteins TIG-3 and Ha-Rev107) harbors an anti-proliferative domain with DNA-binding properties. Dodecapeptides derived from this region showed in vitro growth inhibitory activity in human cutaneous melanoma cells, crossed the plasma membrane, localized to the nucleus, and affected expression of cyclin-dependent kinase-2 and subcellular redistribution of cyclins E and A. Peptide growth inhibition assays, nude mouse tumor model, nuclear localization by fluorescence microscopy, promoter binding assays, CDK2/cyclin expression analysis Carcinogenesis Low 16234259
2038 LRAT enriches DHRS3 at endoplasmic reticulum–lipid droplet contacts juxtaposed to mitochondria after irradiation. Loss of LRAT dispersed these ER-LD-mitochondria interfaces, mislocalized DHRS3, and impaired retinoid and NADPH buffering; enforced mitochondrial targeting of DHRS3 partially restored redox control. This places LRAT as an organizer of a retinoid-coupled NADPH module at ER-LD-mitochondria interfaces. Spatial imaging (proximity/co-localization), LRAT knockdown, enforced mitochondrial DHRS3 targeting, NADP+/NADPH ratio measurements, ROS assays Free radical biology & medicine Low 41579973

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT). The Journal of biological chemistry 251 16115871
2015 Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT). PloS one 59 26656277
2014 LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3. Nature chemical biology 49 25383759
2009 Acidic retinoids synergize with vitamin A to enhance retinol uptake and STRA6, LRAT, and CYP26B1 expression in neonatal lung. Journal of lipid research 44 19700416
2007 Role of LRAT on the retinoid isomerase activity and membrane association of Rpe65. The Journal of biological chemistry 41 17504753
2012 A homozygous frameshift mutation in LRAT causes retinitis punctata albescens. Ophthalmology 38 22559933
2012 Early onset retinal dystrophy due to mutations in LRAT: molecular analysis and detailed phenotypic study. Investigative ophthalmology & visual science 35 22570351
2006 Screening genes of the retinoid metabolism: novel LRAT mutation in leber congenital amaurosis. American journal of ophthalmology 34 17011878
2021 LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene. Journal of lipid research 30 33631212
2016 Hepatic stellate cells retain the capacity to synthesize retinyl esters and to store neutral lipids in small lipid droplets in the absence of LRAT. Biochimica et biophysica acta. Molecular and cell biology of lipids 30 27815220
2007 Somatic ablation of the Lrat gene in the mouse retinal pigment epithelium drastically reduces its retinoid storage. Investigative ophthalmology & visual science 27 18055784
2013 The retinol esterifying enzyme LRAT supports cell signaling by retinol-binding protein and its receptor STRA6. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 24036882
2001 Acyl-CoA: retinol acyltransferase (ARAT) and lecithin:retinol acyltransferase (LRAT) activation during the lipocyte phenotype induction in hepatic stellate cells. The Journal of nutritional biochemistry 22 12031254
1998 Distribution of 11-cis LRAT, 11-cis RD and 11-cis REH in bovine retinal pigment epithelium membranes. Biochimica et biophysica acta 22 9767084
2009 An essential set of basic DNA response elements is required for receptor-dependent transcription of the lecithin:retinol acyltransferase (Lrat) gene. Archives of biochemistry and biophysics 19 19665987
2019 Long-Term Follow-Up of Retinal Degenerations Associated With LRAT Mutations and Their Comparability to Phenotypes Associated With RPE65 Mutations. Translational vision science & technology 18 31448181
2003 Retinoid metabolism (LRAT, REH) in the yolk-sac membrane of Japanese quail eggs and effects of mono-ortho-PCBs. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 16 12524014
2020 Vitamin A deficiency indicating as low expression of LRAT may be a novel biomarker of primary hypertension. Clinical and experimental hypertension (New York, N.Y. : 1993) 15 33052059
2018 A novel LRAT mutation affecting splicing in a family with early onset retinitis pigmentosa. Human genomics 15 29973277
2011 Why some photoreceptors die, while others remain dormant: lessons from RPE65 and LRAT associated retinal dystrophies. Ophthalmic genetics 15 21268677
2003 Retinoids, LRAT and REH activities in eggs of Japanese quail following maternal and in ovo exposures to 3,3',4,4'-tetrachlorobiphenyl. Ecotoxicology (London, England) 14 12739853
2005 Evidence that sequence homologous region in LRAT-like proteins possesses anti-proliferative activity and DNA binding properties: translational implications and mechanism of action. Carcinogenesis 13 16234259
2017 Impact of LCA-Associated E14L LRAT Mutation on Protein Stability and Retinoid Homeostasis. Biochemistry 12 28758396
2021 The Lrat-/- Rat: CRISPR/Cas9 Construction and Phenotyping of a New Animal Model for Retinitis Pigmentosa. International journal of molecular sciences 11 34281288
2014 High incidence of LRAT promoter hypermethylation in colorectal cancer correlates with tumor stage. Medical oncology (Northwood, London, England) 11 25260806
2013 Hepatic stellate cells that coexpress LRAT and CRBP-1 partially contribute to portal fibrogenesis in patients with human viral hepatitis. Liver international : official journal of the International Association for the Study of the Liver 11 23890161
2022 Emergence of highly profibrotic and proinflammatory Lrat+Fbln2+ HSC subpopulation in alcoholic hepatitis. Hepatology (Baltimore, Md.) 9 36181700
2015 LRAT overexpression diminishes intracellular levels of biologically active retinoids and reduces retinoid antitumor efficacy in the murine melanoma B16F10 cell line. Skin pharmacology and physiology 9 25721651
2024 Early activation of hepatic stellate cells induces rapid initiation of retinyl ester breakdown while maintaining lecithin:retinol acyltransferase (LRAT) activity. Biochimica et biophysica acta. Molecular and cell biology of lipids 5 39068984
2023 Fundus Albipunctatus Associated with Biallelic LRAT Gene Mutation: A Case Report with Long-Term Follow-Up. Journal of clinical medicine 5 38002575
2023 The BCO2 Genotype and the Expression of BCO1, BCO2, LRAT, and TTPA Genes in the Adipose Tissue and Brain of Rabbits Fed a Diet with Marigold Flower Extract. International journal of molecular sciences 3 36768627
2014 Transgenic reporter mice with promoter region of murine LRAT specifically marks lens and meiosis spermatocytes. Physiological research 2 25317684
2026 Lrat-Cre Exhibits Widespread Expression Beyond Hepatic Stellate Cells Across Multiple Tissues. bioRxiv : the preprint server for biology 0 41542649
2026 YTHDF2-m6A regulation of DHRS3 at LRAT-organized organelle contacts orchestrates redox to drive radioresistance in esophageal squamous cell carcinoma. Free radical biology & medicine 0 41579973
2026 AAV-mediated gene replacement therapy for LRAT-associated retinitis pigmentosa: a proof-of-concept study in a patient-based rat model. Gene therapy 0 41807804
2026 New genetic feature associated with fundus albipunctatus: case series of two Spanish children with LRAT gene mutation. Documenta ophthalmologica. Advances in ophthalmology 0 42065837
2025 Genetic detection of a novel LRAT pathogenic variant in patients with early-onset severe retinal dystrophy. Ophthalmic genetics 0 40394841
2025 tRF-34-86J8WPMN1E8Y2Q promotes the occurrence and development of gastric cancer by combining with LRAT. Journal of cancer research and clinical oncology 0 41044262

Missed literature

Know a paper Affinage missed for LRAT? Flag it for the maintainers and the community.

No submissions yet.