Affinage

LRAT

Lecithin retinol acyltransferase · UniProt O95237

Length
230 aa
Mass
25.7 kDa
Annotated
2026-04-28
37 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRAT is an endoplasmic reticulum-localized acyltransferase of the N1pC/P60 thioester-intermediate family that catalyzes the esterification of all-trans-retinol using phosphatidylcholine as acyl donor, serving as the predominant physiological route for vitamin A storage in liver, lung, kidney, and retinal pigment epithelium (PMID:16115871, PMID:18055784). Its catalytic specificity arises from a discrete LRAT-specific domain that promotes domain-swapping dimerization and stabilizes the thioester intermediate to favor acyl transfer over hydrolysis (PMID:25383759). By generating retinyl esters, LRAT supplies the obligate substrate for the RPE65 visual-cycle isomerase (PMID:17504753), maintains the retinol concentration gradient required for STRA6/JAK2/STAT5 signaling (PMID:24036882), coordinates ISX-mediated negative-feedback control of intestinal β-carotene conversion (PMID:33631212), and governs lipid droplet size and retinoid homeostasis in hepatic stellate cells (PMID:27815220, PMID:39068984). Loss-of-function mutations such as E14L cause Leber congenital amaurosis through protein destabilization and aberrant retinoic acid accumulation (PMID:28758396).

Mechanistic history

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

    Establishing that LRAT activity resides exclusively in ER membranes of RPE provided the first subcellular framework for compartmentalized retinoid processing in the visual cycle.

    Evidence Subcellular membrane fractionation with ER/PM markers and enzymatic activity assays in bovine RPE

    PMID:9767084

    Open questions at the time
    • Single tissue source (bovine RPE); generalizability to other LRAT-expressing tissues not tested
    • Protein identity not confirmed by immunodetection in fractions
  2. 2001 Medium

    Demonstrating that LRAT induction in hepatic stellate cells is retinoic acid-dependent and distinct from ARAT regulation established that two retinol-esterifying activities are under separate transcriptional control during lipocyte differentiation.

    Evidence Microsomal enzyme kinetics and [³H]retinol metabolite analysis in GRX cells and primary HSCs with retinoic acid treatment

    PMID:12031254

    Open questions at the time
    • Transcriptional mechanism not defined; no promoter analysis performed
    • ARAT molecular identity not established at this time
  3. 2005 High

    The Lrat knockout mouse resolved a long-standing question by showing that LRAT is the predominant retinol esterifying enzyme in vivo, with near-complete loss of retinyl ester stores in liver, lung, kidney, and stellate cell lipid droplets; an alternative ARAT pathway compensates only in adipose tissue.

    Evidence Lrat-/- mice with multi-tissue retinoid HPLC quantification, electron microscopy of stellate cells, fatty acid composition analysis

    PMID:16115871

    Open questions at the time
    • Molecular identity of the compensatory ARAT activity not resolved
    • Contribution of LRAT to retinyl ester formation in intestine not fully defined
  4. 2007 High

    Two complementary studies established that LRAT is required for the visual cycle solely as the source of the retinyl ester substrate for RPE65 isomerase, not for RPE65 membrane association, and that RPE-specific Lrat ablation diminishes ERG responses.

    Evidence Lrat-/- biochemical fractionation with substrate-defined isomerase assays; conditional RPE-specific Lrat knockout with ERG and retinoid HPLC

    PMID:17504753 PMID:18055784

    Open questions at the time
    • Whether residual non-LRAT esterification in RPE can sustain any visual cycle flux remains unclear
    • Kinetic coupling between LRAT and RPE65 at the ER membrane not characterized
  5. 2009 Medium

    Identification of the proximal promoter elements driving retinoic acid-dependent Lrat transcription showed that RAR/RXR activate Lrat through non-canonical regulatory elements (SP3, AP-1, CAAT) rather than classical retinoid response elements.

    Evidence Nuclear run-on, luciferase reporter deletions, and EMSA in HEK293T and HepG2 cells

    PMID:19665987

    Open questions at the time
    • Intermediary factors bridging RAR/RXR to the proximal promoter not identified
    • In vivo chromatin occupancy not tested
  6. 2013 High

    Linking LRAT to STRA6/JAK2/STAT5 signaling expanded its role beyond retinoid storage to active signal transduction: LRAT-driven retinol uptake is required for STRA6 to function as a cytokine receptor, and Lrat-null mice are protected from holo-RBP-induced insulin resistance.

    Evidence Lrat-null mice, cell-based STRA6/JAK2/STAT5 signaling assays, and insulin response measurements

    PMID:24036882

    Open questions at the time
    • Whether LRAT physically associates with STRA6 or acts purely through metabolic gradient not resolved
    • Tissue-specific contribution of LRAT to STRA6 signaling beyond the examined systems unknown
  7. 2014 High

    A 2.2-Å crystal structure of a LRAT-domain chimera in the thioester intermediate state revealed how a discrete LRAT-specific domain confers acyltransferase specificity within the N1pC/P60 family by promoting domain-swapping dimerization that slows thioester hydrolysis.

    Evidence Gain-of-function domain-swap chimera (LRAT-LD into HRASLS3), 2.2-Å crystal structure, in vitro enzymatic assays

    PMID:25383759

    Open questions at the time
    • Structure is of a chimeric protein, not full-length LRAT; native LRAT structure unavailable
    • Membrane-associated conformation and retinol binding geometry not determined
  8. 2015 Medium

    Demonstrating that LRAT overexpression diverts retinol away from retinoic acid synthesis confirmed a metabolic branch-point function: LRAT activity attenuates RAR-regulated gene expression and the antiproliferative effects of retinoids.

    Evidence Stable LRAT overexpression in B16F10 melanoma cells, HPLC retinoid quantification, RT-PCR for Cyp26a1

    PMID:25721651

    Open questions at the time
    • Overexpression system; physiological relevance of the branch-point ratio in non-transformed cells not established
    • No loss-of-function complement in the same system
  9. 2016 High

    Quantitative lipidomics in Lrat-/- hepatic stellate cells showed that DGAT1 provides a compensatory retinyl ester synthesis pathway but produces smaller lipid droplets, establishing that LRAT determines lipid droplet size and the specific retinyl ester species profile.

    Evidence Lrat-/- primary HSC cultures, LC-MS/MS MRM retinyl ester quantification, lipid droplet morphometry

    PMID:27815220

    Open questions at the time
    • Mechanism by which LRAT-derived esters promote larger droplets (biophysical or protein-scaffolding) not defined
    • In vivo hepatic stellate cell activation dynamics not captured in culture
  10. 2017 Medium

    Characterization of the LCA-associated E14L mutation showed it destabilizes LRAT protein via proteasomal degradation and paradoxically increases retinoic acid accumulation, suggesting that disease pathology involves retinoic acid toxicity rather than simple loss of chromophore production.

    Evidence Bicistronic LRAT(E14L)-EGFP stability assays, proteasome inhibitor experiments, cell-based chromophore production and HPLC retinoid quantification

    PMID:28758396

    Open questions at the time
    • Retinoic acid toxicity mechanism not validated in vivo
    • Whether other LCA-associated LRAT mutations share this gain-of-toxicity pathomechanism unknown
  11. 2021 High

    Genetic epistasis between Lrat and Isx revealed that LRAT-mediated retinol sequestration coordinates intestinal β-carotene absorption through a negative-feedback loop: without LRAT, ISX becomes hypersensitive to dietary vitamin A and suppresses β-carotene oxygenase, causing extrahepatic vitamin A deficiency.

    Evidence Lrat-/- mice, Isx-/- double-knockout epistasis, pharmacological retinoid signaling inhibition, tissue retinoid quantification

    PMID:33631212

    Open questions at the time
    • Whether LRAT in enterocytes directly esterifies retinol or acts indirectly through circulating retinoid pool not fully separated
    • Quantitative contribution of this feedback loop relative to hepatic retinoid homeostasis not established
  12. 2024 Medium

    Temporal profiling of stellate cell activation resolved that early activation maintains LRAT activity while increasing retinyl ester hydrolysis, with LRAT loss and DGAT1 compensation occurring only during prolonged activation.

    Evidence HSCs cultured on soft gel vs. stiff substrates, Lrat mRNA/protein kinetics, LC-MS/MS retinyl ester analysis

    PMID:39068984

    Open questions at the time
    • In vivo validation of the two-phase model in liver fibrosis progression not performed
    • Identity of the hydrolase(s) responsible for early retinyl ester breakdown not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structure of membrane-embedded LRAT, the identity and regulation of the retinyl ester hydrolase(s) that oppose LRAT activity, and whether LRAT has a direct protein-scaffolding role at ER–lipid droplet contacts remain unresolved.
  • No structure of full-length, membrane-associated LRAT is available
  • Retinyl ester hydrolase opposing LRAT in stellate cells and RPE molecularly unidentified
  • Proposed ER–lipid droplet contact site scaffolding role (PMID:41579973) is from a single study and awaits independent confirmation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5
Localization
GO:0005811 lipid droplet 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-9709957 Sensory Perception 2 R-HSA-162582 Signal Transduction 1
Partners
DGAT1DHRS3HRASLS3ISXRPE65STRA6

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 LRAT is the predominant enzyme responsible for physiological esterification of retinol in liver, lung, and kidney; Lrat-/- mice lack retinyl ester stores in these tissues and hepatic stellate cell lipid droplets, confirming LRAT's essential role. In adipose tissue, an acyl-CoA-dependent acyl-CoA:retinol acyltransferase (ARAT) compensates, as evidenced by the fatty acyl composition of chylomicron retinyl esters in Lrat-/- mice. Lrat knockout mouse model with tissue retinoid quantification, electron microscopy of stellate cells, and fatty acid composition analysis of retinyl esters The Journal of biological chemistry High 16115871
2014 A specific LRAT-specific domain (LRAT-LD) confers substrate specificity to N1pC/P60 family enzymes. When swapped into HRASLS3, this domain causes three-dimensional domain-swapping dimerization and slows hydrolysis of the thioester catalytic intermediate, enabling efficient acyl transfer to retinol rather than phospholipid hydrolysis. A 2.2-Å crystal structure of the chimeric enzyme in a thioester intermediate state revealed the structural basis for this catalytic diversity. Gain-of-function domain-swap chimera, 2.2-Å crystal structure of thioester intermediate, in vitro enzymatic assays Nature chemical biology High 25383759
2007 LRAT is not required for the membrane association of RPE65 or its palmitoylation; RPE65 membrane affinity is similar in wild-type and Lrat-/- mice. LRAT is required for isomerase activity only insofar as it synthesizes the retinyl ester substrate: with all-trans-retinyl palmitate as substrate, isomerase activity is equivalent in both genotypes, but with all-trans-retinol, isomerase activity is undetectable in Lrat-/- RPE because retinyl esters are absent. Lrat-/- mouse biochemical fractionation, isomerase activity assays with defined substrates, mass spectrometry for palmitoylation, 2-bromopalmitate inhibition The Journal of biological chemistry High 17504753
1998 In bovine RPE, LRAT activity is exclusively localized to endoplasmic reticulum-enriched membranes, whereas 11-cis retinyl ester hydrolase (REH) is predominantly in plasma membrane fractions, establishing compartmentalized retinoid processing within RPE subcellular membranes. Subcellular membrane fractionation with ER and PM marker enrichment, enzymatic activity assays on fractions Biochimica et biophysica acta Medium 9767084
2001 Both LRAT and acyl-CoA:retinol acyltransferase (ARAT) activities are induced during conversion of hepatic stellate cell myofibroblasts to lipocytes. LRAT induction is dependent on retinoic acid, whereas ARAT induction depends on the overall fat-storing phenotype, demonstrating distinct transcriptional regulation of the two retinol esterifying enzymes. Microsomal enzyme kinetics, [3H]retinol metabolite analysis in GRX cell line and primary HSCs, retinoic acid treatment The Journal of nutritional biochemistry Medium 12031254
2007 RPE-specific somatic ablation of Lrat strongly reduces all-trans retinyl ester synthesis in RPE cells and diminishes ERG light responses, confirming that LRAT in the RPE is the primary source of retinyl ester substrate for the visual cycle. Conditional Cre-lox knockout (Tyrp1-Cre driving RPE-specific Lrat deletion), retinoid HPLC quantification, ERG recordings Investigative ophthalmology & visual science High 18055784
2013 LRAT-catalyzed esterification of retinol is necessary for STRA6-mediated activation of JAK2/STAT5 signaling by holo-RBP. By maintaining an inward retinol concentration gradient, LRAT enables STRA6-mediated retinol transport, which in turn supports STRA6 cytokine receptor function. LRAT-null mice are protected from holo-RBP-induced suppression of insulin signaling. LRAT-null mice, cell-based STRA6/JAK2/STAT5 signaling assays, insulin response measurements FASEB journal High 24036882
2021 LRAT's catalytic sequestration of retinol into retinyl esters coordinates the negative-feedback regulation of intestinal β-carotene conversion to vitamin A. In LRAT-deficient mice, the transcription factor ISX becomes hypersensitive to dietary vitamin A and suppresses β-carotene oxygenase-1, leading to β-carotene accumulation and extrahepatic vitamin A deficiency. Pharmacological inhibition of retinoid signaling or Isx gene deletion restores retinoid biosynthesis. Lrat-/- mice, pharmacological retinoid signaling inhibition, Isx-/- genetic epistasis, tissue retinoid quantification Journal of lipid research High 33631212
2016 In the absence of LRAT, quiescent hepatic stellate cells retain the capacity to synthesize retinyl esters via DGAT1, but lipid droplets are significantly smaller (median 1080 nm vs. 1618 nm in WT). During HSC activation, the cell shifts retinyl ester synthesis from LRAT to DGAT1, as shown by exogenous fatty acid incorporation into retinyl ester species. Lrat-/- primary HSC cultures, LC-MS/MS MRM quantification of retinyl ester species, lipid droplet size measurement Biochimica et biophysica acta. Molecular and cell biology of lipids High 27815220
2017 The LCA-associated E14L mutation in LRAT destabilizes the protein and causes accelerated proteasomal degradation. Despite reduced protein levels, some visual chromophore production persists in a cell-based assay. Instead, E14L expression leads to rapid increase in cellular retinoic acid upon retinoid supplementation, implicating retinoic acid toxicity in the disease pathology. Bicistronic LRAT(E14L)-EGFP expression for protein stability, proteasome inhibitor experiments, cell-based chromophore production assay, HPLC retinoid quantification Biochemistry Medium 28758396
2015 LRAT overexpression in murine melanoma B16F10 cells increases retinyl ester levels, reduces intracellular all-trans-retinol and ATRA, decreases RAR-regulated Cyp26a1 expression, and diminishes the antiproliferative effects of retinoid treatment, establishing that LRAT-catalyzed esterification diverts retinol away from retinoic acid signaling. Stable LRAT overexpression in B16F10 cells, HPLC retinoid quantification, cell viability assays, RT-PCR for Cyp26a1 Skin pharmacology and physiology Medium 25721651
2024 During early hepatic stellate cell activation, LRAT activity and retinyl ester formation are maintained while retinyl ester levels decline due to enhanced breakdown (hydrolysis). Only upon prolonged activation is LRAT activity lost, at which point residual retinyl ester synthesis shifts to DGAT1. HSCs cultured in soft gel (quiescent) vs. stiff plastic (activated), Lrat mRNA/protein quantification, LC-MS/MS retinyl ester analysis, comparison of RE synthesis and breakdown rates Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 39068984
2009 Transcriptional regulation of the rat Lrat gene by retinoic acid (RA) requires a proximal promoter region (~300 bp upstream of TSS) containing essential basic elements (TATA box, SP3 site, AP-1 site, CAAT box); nuclear run-on assays confirmed transcriptional (not post-transcriptional) activation by RA. RAR/RXR receptors drive Lrat expression via this region despite absence of canonical retinoid response elements. Nuclear run-on transcription assay, luciferase reporter deletions in HEK293T and HepG2 cells, electrophoretic mobility shift assay with nuclear extracts Archives of biochemistry and biophysics Medium 19665987
2026 LRAT enriches DHRS3 at endoplasmic reticulum–lipid droplet interfaces juxtaposed to mitochondria after irradiation; loss of LRAT disperses these organelle contacts, mislocalizes DHRS3, and impairs retinoid and NADPH buffering, contributing to radioresistance in esophageal squamous cell carcinoma. Spatial imaging (ER-LD-mitochondria contacts), LRAT knockdown/overexpression, DHRS3 mitochondrial targeting rescue, NADP+/NADPH measurement, ROS quantification, clonogenic survival Free radical biology & medicine Low 41579973

Source papers

Stage 0 corpus · 37 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 249 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 58 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 40 17504753
2012 A homozygous frameshift mutation in LRAT causes retinitis punctata albescens. Ophthalmology 37 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
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
2021 LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene. Journal of lipid research 29 33631212
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
2011 Why some photoreceptors die, while others remain dormant: lessons from RPE65 and LRAT associated retinal dystrophies. Ophthalmic genetics 15 21268677
2018 A novel LRAT mutation affecting splicing in a family with early onset retinitis pigmentosa. Human genomics 14 29973277
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 4 39068984
2023 Fundus Albipunctatus Associated with Biallelic LRAT Gene Mutation: A Case Report with Long-Term Follow-Up. Journal of clinical medicine 4 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
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