Affinage

SLC27A5

Long-chain fatty acid transport protein 5 · UniProt Q9Y2P5

Length
690 aa
Mass
75.4 kDa
Annotated
2026-06-10
21 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: UniProt preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC27A5 (FATP5) is a liver-specific, basal plasma membrane bifunctional protein that mediates hepatocellular long-chain fatty acid (LCFA) uptake and functions as a bile acid-CoA ligase required for bile acid reconjugation (PMID:16618416, PMID:21826528). Its acyl-CoA synthetase activity also supplies fatty acyl-CoA intermediates upstream of BAAT for hepatic N-acyl taurine synthesis (PMID:41780593). Transcription of SLC27A5 is activated by HNF4A and PPARα and repressed by RUNX2 and by hypoxia (PMID:37957540, PMID:39938688, PMID:42202975), while its protein level is controlled by UBAP2-mediated ubiquitin-proteasome degradation (PMID:39186963). In hepatocellular carcinoma SLC27A5 acts as a tumor suppressor whose loss reshapes lipid and redox metabolism: depletion elevates polyunsaturated lipids and lipid peroxidation, generating 4-HNE that modifies KEAP1 at Cys513/Cys518 to activate NRF2 target genes including TXNRD1 and GSR, sustaining glutathione homeostasis and conferring ferroptosis and sorafenib resistance (PMID:31367013, PMID:36635256). SLC27A5 loss also drives a glycolytic shift that suppresses AMPK and activates mTOR to promote epithelial-mesenchymal transition (PMID:34772914), and accumulated unconjugated cholic acid activates hepatic stellate cells via EGR3 to drive liver fibrosis (PMID:37957540). Beyond metabolism, SLC27A5 sequesters IGF2BP3 in the cytoplasm to control PIP4K2A alternative splicing and PI3K signaling, and lowers PABPC1 to shift METTL14 alternative polyadenylation, together restraining metastasis and cancer stem cell stemness (PMID:38059827, PMID:40290127). Reduced SLC27A5 in tumors with impaired LCFA oxidation represents a survival adaptation that redirects fatty acid biosynthesis toward the glutamine reductive pathway, creating a therapeutic vulnerability to glutaminase inhibition (PMID:42202975).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Established that FATP5 is the required mediator of hepatocellular LCFA uptake, defining its core physiological function and tissue restriction.

    Evidence Knockout mouse and overexpression with 14C-oleate uptake plus immunolocalization to hepatocyte basal plasma membrane

    PMID:16618416

    Open questions at the time
    • Did not resolve the catalytic mechanism coupling uptake to acyl-CoA synthesis
    • No structural model of the transporter/enzyme
  2. 2011 Medium

    Demonstrated FATP5's enzymatic role in bile acid reconjugation in vivo and bounded its contribution to hepatic steatosis.

    Evidence In vivo knockdown with bile acid profiling and hepatic triglyceride measurement

    PMID:21826528

    Open questions at the time
    • Did not identify the bile acid-CoA ligase active site
    • Knockdown rather than full ablation
  3. 2019 High

    Showed that SLC27A5 loss links lipid peroxidation to redox signaling via a specific 4-HNE modification of KEAP1, explaining NRF2 activation in HCC.

    Evidence Reciprocal gain/loss-of-function in HCC cells with MS identification of 4-HNE-modified KEAP1 Cys513/518 and in vivo tumor models

    PMID:31367013

    Open questions at the time
    • Did not establish whether NRF2 activation is sufficient for tumor suppression reversal
    • Other 4-HNE targets not excluded
  4. 2021 Medium

    Placed SLC27A5 upstream of the AMPK/mTOR axis, connecting its metabolic role to EMT and invasion.

    Evidence Knockdown/overexpression with glycolysis and ATP assays, AMPK/mTOR phosphorylation, and metformin rescue in vitro and in vivo

    PMID:34772914

    Open questions at the time
    • Mechanism linking LCFA uptake loss to glycolytic flux not fully defined
    • Single lab
  5. 2023 Medium

    Defined the NRF2/GSR/GSH axis through which SLC27A5 loss suppresses ferroptosis and confers sorafenib resistance, and identified a re-sensitizing strategy.

    Evidence Knockout/knockdown HCC cells with GSH measurement, ferroptosis assays, and sorafenib+BCNU combination in vivo

    PMID:36635256

    Open questions at the time
    • Clinical translatability of GSR inhibition untested
    • Single lab
  6. 2023 High

    Connected SLC27A5 deficiency to fibrosis via cholic acid accumulation activating stellate cells through EGR3, and identified RUNX2 as a transcriptional repressor.

    Evidence Knockout mouse fibrosis models, bile acid profiling, HSC activation assays, AAV and ASBT-inhibitor rescue, RUNX2 ChIP/reporter

    PMID:37957540

    Open questions at the time
    • Direct EGR3 effector mechanism in HSCs not fully resolved
    • Human fibrosis correlation limited
  7. 2023 Medium

    Revealed a non-canonical RNA-regulatory function whereby SLC27A5 sequesters IGF2BP3 to control PIP4K2A splicing and PI3K signaling in metastasis.

    Evidence Reciprocal Co-IP, subcellular fractionation, RNA-seq splicing analysis, p85 stability assays, and AAV/RNA-decoy rescue

    PMID:38059827

    Open questions at the time
    • How a metabolic enzyme binds IGF2BP3 structurally unknown
    • Single lab
  8. 2024 Medium

    Identified UBAP2 as an E3-pathway driver of SLC27A5 degradation linking its turnover to RAD51-mediated homologous recombination and radioresistance.

    Evidence UBAP2 knockdown/overexpression, SLC27A5 rescue, ubiquitin-proteasome assays, RAD51/CTIP expression, and in vivo radiation assays

    PMID:39186963

    Open questions at the time
    • Specific ubiquitination sites on SLC27A5 not mapped
    • Direct vs indirect UBAP2 action not distinguished
  9. 2024 High

    Extended FATP5's fatty acid uptake role to a tumor-supporting function in intrahepatic cholangiocarcinoma growth.

    Evidence Knockout mice and AAV-shRNA silencing with in vivo FFA-Luc uptake monitoring and lipidomics

    PMID:38358323

    Open questions at the time
    • Apparent context-dependent opposite roles (suppressor in HCC, pro-growth in ICC) not mechanistically reconciled
  10. 2024 Medium

    Showed SLC27A5 modulates METTL14 alternative polyadenylation via PABPC1 to suppress cancer stem cell stemness, broadening its RNA-regulatory reach.

    Evidence IP-MS, RNA-seq APA analysis, isoform-specific expression, and stemness assays with overexpression/knockdown

    PMID:40290127

    Open questions at the time
    • Whether PABPC1 regulation is direct unclear
    • Single lab
  11. 2025 Medium

    Established that hypoxia represses SLC27A5 via HNF4A, with loss activating AKT and G1-to-S transition, and proposed a combination therapy.

    Evidence Hypoxia models, HNF4A knockdown/overexpression, promoter reporters, cell cycle analysis, and Benfluorex+MK2206 xenografts

    PMID:39938688

    Open questions at the time
    • Mechanism linking SLC27A5 loss to AKT activation undefined
    • Single lab
  12. 2025 Medium

    Defined a FATP5→PUFA-lipid→SREBP1/SCD1 axis in MASH, showing knockdown is protective by relieving ferroptotic lipid pressure.

    Evidence Knockdown and MCD-diet MASH model, untargeted lipidomics, SREBP1/SCD1 analysis, ferrostatin-1, and AAV-SCD1 rescue

    PMID:40840619

    Open questions at the time
    • Whether protective knockdown effect generalizes beyond MCD model unknown
    • Single lab
  13. 2026 Medium

    Assigned FATP5 an upstream role in hepatic N-acyl taurine synthesis through its acyl-CoA synthetase activity, overlapping with bile acid conjugation.

    Evidence Transcriptomics in NAT hydrolase-deficient mice and in vivo Slc27a5 knockdown with NAT and bile acid metabolite profiling

    PMID:41780593

    Open questions at the time
    • Direct biochemical demonstration of acyl-CoA intermediate generation in vitro absent
    • Single lab
  14. 2026 Medium

    Showed PPARα represses SLC27A5 in HCC with impaired LCFA oxidation, with low SLC27A5 redirecting biosynthesis to the glutamine reductive pathway and creating glutaminase-inhibitor sensitivity.

    Evidence PPARα knockdown/agonist, promoter reporters, metabolic flux analysis, and glutaminase inhibitor sensitivity assays

    PMID:42202975

    Open questions at the time
    • Apparent discrepancy with PPARα as activator elsewhere not reconciled
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SLC27A5 functions both as a tumor suppressor in HCC and a pro-growth fatty acid supplier in ICC, and how its enzymatic versus non-canonical RNA-regulatory activities are partitioned, remain unresolved.
  • No structural basis for dual transporter/ligase and IGF2BP3-binding functions
  • Context-dependent transcriptional control by PPARα (activator vs repressor) unexplained
  • No human genetic disease link established in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0005215 transporter activity 2 GO:0016874 ligase activity 2 GO:0016740 transferase activity 1
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-1430728 Metabolism 4 R-HSA-8953854 Metabolism of RNA 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
BAATIGF2BP3KEAP1PABPC1UBAP2

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 FATP5 (SLC27A5) is exclusively expressed in liver and localizes to the basal plasma membrane of hepatocytes. Knockout of FATP5 significantly reduced long-chain fatty acid (LCFA) uptake by isolated hepatocytes, and overexpression increased 14C-oleate uptake in mammalian cells, establishing FATP5 as a required mediator of hepatocellular LCFA uptake. FATP5 knockout mouse model (hepatocyte isolation/uptake assays), overexpression with 14C-oleate uptake, immunolocalization Gastroenterology High 16618416
2011 Fatp5 knockdown in mice increased the proportion of unconjugated bile acids ~100-fold, confirming FATP5's enzymatic role in bile acid reconjugation in vivo. However, Fatp5 knockdown did not alleviate ApoB-siRNA-induced hepatic triglyceride accumulation, indicating FATP5-mediated fatty acid uptake is not the dominant pathway for this form of steatosis. siRNA/shRNA knockdown of Fatp5 in mice; bile acid profiling; hepatic triglyceride measurement Lipids Medium 21826528
2019 SLC27A5 knockout in hepatoma cells increases polyunsaturated lipids, elevates NADP+/NADPH ratio, ROS, and lipid peroxidation, leading to 4-HNE accumulation. Mass spectrometry showed 4-HNE directly modifies cysteine residues Cys513 and Cys518 on KEAP1, activating the KEAP1/NRF2 pathway and upregulating NRF2 target genes including TXNRD1. SLC27A5 gain- and loss-of-function in HCC cells; mass spectrometry identification of 4-HNE-modified KEAP1 cysteines; NRF2/TXNRD1 expression assays; in vivo tumor models Cell death and differentiation High 31367013
2021 FATP5 knockdown in HCC cells promotes glycolytic flux and ATP production, suppressing AMPK activity and activating downstream mTOR signaling to support epithelial-mesenchymal transition, migration, and invasion. Metformin-mediated AMPK activation reversed EMT in FATP5-depleted cells, placing FATP5 upstream of the AMPK/mTOR axis. FATP5 knockdown/overexpression in HCC cells; glycolytic flux and ATP assays; AMPK/mTOR phosphorylation analysis; metformin rescue experiment; in vivo mouse models Oncogenesis Medium 34772914
2023 SLC27A5 loss enhances glutathione reductase (GSR) expression in an NRF2-dependent manner, maintaining GSH homeostasis and suppressing ferroptosis, thereby conferring sorafenib resistance. Genetic or pharmacological GSR inhibition (BCNU/carmustine) depleted GSH and restored lipid peroxide accumulation, re-sensitizing SLC27A5-knockout HCC cells to sorafenib-induced ferroptosis. SLC27A5 knockout and knockdown in HCC cells; GSR expression and GSH measurement; ferroptosis assays; in vivo tumor growth with sorafenib + BCNU combination Cell death & disease Medium 36635256
2023 SLC27A5 deficiency results in accumulation of unconjugated bile acids—particularly cholic acid (CA)—in the liver. Accumulated CA activates hepatic stellate cells (HSCs) by upregulating EGR3 expression, driving liver fibrosis. AAV-mediated SLC27A5 re-expression or reduction of CA levels with ASBT inhibitor A4250 ameliorated fibrosis in Slc27a5-/- mice. RUNX2 was identified as a transcriptional repressor of SLC27A5. Slc27a5 knockout mice; CCl4/TAA-induced fibrosis models; bile acid profiling; HSC activation assays; AAV rescue; ASBT inhibitor treatment; RUNX2 ChIP/reporter assays Advanced science High 37957540
2023 SLC27A5 exerts a non-canonical function by interacting with IGF2BP3 to prevent its nuclear translocation, thereby inhibiting IGF2BP3 binding to target mRNA and modulating alternative splicing of PIP4K2A pre-mRNA. Loss of SLC27A5 elevates the PIP4K2A-S isoform, which enhances p85 stability and activates PI3K signaling to promote HCC metastasis. Co-immunoprecipitation; subcellular fractionation; alternative splicing analysis by RNA-seq; IGF2BP3 knockdown/overexpression; p85 stability assays; AAV-Slc27a5 rescue; RNA decoy oligonucleotides Advanced science Medium 38059827
2024 UBAP2, through the ubiquitin-proteasome system, degrades SLC27A5, leading to decreased RAD51 expression (homologous recombination) and radioresistance in HCC. Ectopic SLC27A5 expression reversed the radioresistance conferred by UBAP2, establishing SLC27A5 as a substrate of UBAP2-mediated ubiquitin-proteasome degradation. UBAP2 knockdown/overexpression; SLC27A5 rescue experiments; ubiquitin-proteasome pathway assays; RAD51 and CTIP expression analysis; in vitro and in vivo radiation resistance assays Biochimica et biophysica acta. Molecular basis of disease Medium 39186963
2024 FATP5 is the predominant mediator of fatty acid uptake required for intrahepatic cholangiocarcinoma (ICC) growth in vivo. Fatp5 knockout mice and AAV-based shRNA silencing of Fatp5 both suppressed ICC tumor growth, and lipidomics confirmed dramatically elevated fatty acid levels in ICC. Fatp5 knockout mice; AAV-shRNA silencing; luciferase-based fatty acid uptake monitoring in vivo (FFA-Luc); lipidomics Molecular cancer research High 38358323
2024 SLC27A5 reduces expression of PABPC1, an alternative polyadenylation (APA)-associated factor, thereby promoting use of the proximal polyadenylation site of METTL14 mRNA. This produces the METTL14-US isoform, which escapes miRNA-mediated repression due to a shorter 3'UTR, increasing METTL14 protein and suppressing HCC cancer stem cell stemness. Immunoprecipitation-mass spectrometry; RNA-seq for APA events; SLC27A5 overexpression/knockdown; PABPC1 expression analysis; isoform-specific expression assays; stemness assays Genes & diseases Medium 40290127
2025 Hypoxia suppresses SLC27A5 transcription by repressing hepatocyte nuclear factor 4 alpha (HNF4A). Loss of SLC27A5 activates the AKT pathway, increases CDK2 and Cyclin E1 expression, and promotes G1-to-S phase transition in HCC cells. HNF4A activation by Benfluorex combined with AKT inhibitor MK2206 synergistically inhibited HCC xenograft growth. In vitro and in vivo hypoxia models; HNF4A knockdown/overexpression; SLC27A5 promoter reporter assays; cell cycle analysis; AKT pathway phosphorylation; xenograft model with pharmacological combination Biochimica et biophysica acta. Molecular cell research Medium 39938688
2025 FATP5 knockdown in MASH models reduces pro-ferroptotic PUFA-containing lipids, which alleviates suppression of SREBP1, subsequently upregulating its transcriptional target SCD1 (stearoyl-CoA desaturase 1). AAV-mediated SCD1 overexpression in vivo attenuated hepatic inflammation and liver injury in MASH by inhibiting ferroptosis, identifying a FATP5→PUFA-lipids→SREBP1/SCD1 axis. FATP5 knockdown in vitro and MCD diet-induced MASH mouse model; untargeted lipidomics; SREBP1/SCD1 expression analysis; ferroptosis inhibitor (ferrostatin-1) treatment; AAV-SCD1 in vivo overexpression Free radical biology & medicine Medium 40840619
2026 FATP5 is necessary for hepatic N-acyl taurine (NAT) synthesis, acting upstream of BAAT through its acyl-CoA synthetase activity to generate fatty acyl-CoA intermediates. In vivo knockdown of Slc27a5 confirmed that FATP5 is required for hepatic NAT synthesis, identifying a functional overlap between hepatic NAT and bile acid conjugation pathways. Liver transcriptomics in NAT hydrolase-deficient mice; in vivo siRNA/shRNA knockdown of Slc27a5; NAT and bile acid metabolite profiling Journal of lipid research Medium 41780593
2026 In HCC cells with impaired LCFA oxidation, SLC27A5 downregulation is driven by suppressed PPARα signaling (which represses SLC27A5 transcription). Loss of SLC27A5 reduces LCFA uptake, preventing lipotoxicity from unutilized LCFAs. HCC cells with low SLC27A5 compensate by relying on the glutamine reductive pathway for fatty acid biosynthesis, rendering them sensitive to glutaminase inhibition. SLC27A5 overexpression/knockdown in HCC cells; PPARα knockdown and agonist treatment; SLC27A5 promoter reporter assays; metabolic flux analysis (glutamine reductive pathway); glutaminase inhibitor sensitivity assays Cancer letters Medium 42202975
2026 Sesaminol enhances PPARα occupancy on the Slc27a5 promoter, increasing SLC27A5-mediated fatty acid uptake and restoring mitochondrial β-oxidation flux, linking PPARα as a direct transcriptional activator of SLC27A5 in hepatic lipid metabolism. ChIP assay (PPARα on Slc27a5 promoter); transcriptomic analysis; in vitro HepG2 and in vivo HFD/alcohol mouse models; molecular docking Molecular nutrition & food research Low 42170787

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology 202 16618416
2019 SLC27A5 deficiency activates NRF2/TXNRD1 pathway by increased lipid peroxidation in HCC. Cell death and differentiation 101 31367013
2023 SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase. Cell death & disease 81 36635256
2020 Bile acids mediated potential functional interaction between FXR and FATP5 in the regulation of Lipid Metabolism. International journal of biological sciences 61 32760200
2019 Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients. Journal of gastroenterology 48 31602526
2022 Decreased SLC27A5 Suppresses Lipid Synthesis and Tyrosine Metabolism to Activate the Cell Cycle in Hepatocellular Carcinoma. Biomedicines 34 35203444
2021 Fatty acid transport protein-5 (FATP5) deficiency enhances hepatocellular carcinoma progression and metastasis by reprogramming cellular energy metabolism and regulating the AMPK-mTOR signaling pathway. Oncogenesis 31 34772914
2011 ApoB siRNA-induced liver steatosis is resistant to clearance by the loss of fatty acid transport protein 5 (Fatp5). Lipids 31 21826528
2023 Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 26 37957540
2023 Metabolic Enzyme SLC27A5 Regulates PIP4K2A pre-mRNA Splicing as a Noncanonical Mechanism to Suppress Hepatocellular Carcinoma Metastasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 15 38059827
2023 Copper metabolism-related risk score identifies hepatocellular carcinoma subtypes and SLC27A5 as a potential regulator of cuproptosis. Aging 11 38157255
2024 UBAP2 contributes to radioresistance by enhancing homologous recombination through SLC27A5 ubiquitination in hepatocellular carcinoma. Biochimica et biophysica acta. Molecular basis of disease 8 39186963
2024 FATP5 Is Indispensable for the Growth of Intrahepatic Cholangiocarcinoma. Molecular cancer research : MCR 7 38358323
2025 FATP5 deficiency alleviates MASH via remodeling hepatic lipid composition to suppress ferroptosis. Free radical biology & medicine 5 40840619
2024 FATP5 modulates biological activity and lipid metabolism in prostate cancer through the TEAD4-mediated Hippo signaling. Frontiers in oncology 4 39224804
2025 Hypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A. Biochimica et biophysica acta. Molecular cell research 3 39938688
2024 SLC27A5 inhibits cancer stem cells by inducing alternative polyadenylation of METTL14 in hepatocellular carcinoma. Genes & diseases 2 40290127
2026 The bile acid-CoA ligase, FATP5, is necessary for the synthesis of N-acyl taurines in the liver. Journal of lipid research 0 41780593
2026 Sesaminol Ameliorates Metabolic and Alcohol-Related Liver Injury by Activating the PPARα/Slc27a5 Axis-Driven Hepatic Fatty Acid β-Oxidation. Molecular nutrition & food research 0 42170787
2026 SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma. Cancer letters 0 42202975
2025 In vivo protein half-life analysis identifies the SREBF1-SLC27a5 axis governs antioxidant response in preclinical alcoholic rat model. Redox biology 0 40516455

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