Affinage

THRSP

Thyroid hormone-inducible hepatic protein · UniProt Q92748

Length
146 aa
Mass
16.6 kDa
Annotated
2026-06-10
34 papers in source corpus 15 papers cited in narrative 15 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

THRSP (Spot14) is a nuclear lipogenic protein that acts as a direct regulator of fatty acid synthesis enzymes and is required for de novo lipogenesis in vivo (PMID:24771867, PMID:19356628). It directly enhances FASN catalytic activity, increasing medium-chain fatty acid (C14:0) yield in reconstitution assays, with add-back of purified Spot14 rescuing the diminished FASN activity of Spot14-null lysates (PMID:24771867). As a heterocomplex with its paralog Mig12, THRSP binds ACC2, blocks its citrate-induced filamentous polymerization, and restrains its carboxylase activity, with the full heterocomplex serving as the designated inhibitor (PMID:24277613). Genetically, Thrsp is required for de novo lipogenesis in the lactating mammary gland (PMID:19356628), and its overexpression in mammary epithelial cells upregulates lipogenic genes (FASN, SCD1, DGAT2, GPAM) and raises triacylglycerol and medium-chain fatty acid content (PMID:26851858). In adipocytes THRSP is induced by insulin via PI3K and supports mitochondrial respiration, fatty acid oxidation, and sphingolipid (hexosylceramide) homeostasis (PMID:35715726). THRSP expression is controlled by carbohydrate/glucose signaling through ChREBP binding and histone acetylation at its promoter (PMID:21244091) and by NF-Y binding at an inverted CCAAT element required for basal promoter activity (PMID:10830504). Beyond lipogenesis, THRSP has neural roles: it is induced during the early phase of NMDA-receptor-dependent long-term potentiation and is required for LTP induction (PMID:11811657), and its striatal overexpression produces an inattentive phenotype with altered dopamine-pathway gene expression that is normalized by methylphenidate (PMID:30138648).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 Medium

    Established how the Spot14 promoter achieves basal activity, identifying a defined cis-element and trans-factor controlling its expression.

    Evidence EMSA and in vitro transcription/translation showing NF-Y binding at the inverted CCAAT element at -100 of the rat Spot14 promoter

    PMID:10830504

    Open questions at the time
    • Does not address hormone- or nutrient-responsive regulation
    • Single promoter context in rat
  2. 2001 Medium

    Placed THRSP in neural plasticity by showing it is an NMDA-receptor-dependent early-phase LTP gene required for LTP induction.

    Evidence Antisense knockdown, MK801 NMDA blockade, in situ hybridization, and in vivo LTP recording in rat dentate gyrus

    PMID:11811657

    Open questions at the time
    • Molecular mechanism downstream of THRSP in LTP unknown
    • No link to its lipogenic function
  3. 2003 Medium

    Tested whether THRSP mediates thyroid hormone effects in neurons, showing it drives cell death and links T3 to cytotoxicity.

    Evidence THRP overexpression in PC12 cells with TUNEL, PI/Hoechst, thymidine incorporation, and c-Abl co-expression controls

    PMID:12698219

    Open questions at the time
    • Mechanism of cell death not resolved
    • c-Abl interaction tested negative
    • Cell-line context only
  4. 2004 Medium

    Extended the neuronal cytotoxicity finding to primary neurons, confirming THRSP as a mediator of thyroid hormone-induced neuronal death.

    Evidence THRP overexpression in primary rat embryonic neurons with PI staining, LDH release, and survival assays

    PMID:15490139

    Open questions at the time
    • Pathway linking THRSP to death not defined
    • Physiological relevance of overexpression unclear
  5. 2009 High

    Provided in vivo proof that THRSP is required for de novo lipogenesis, defining a tissue-specific physiological role.

    Evidence Thrsp knockout mouse phenotyping showing mammary gland lipogenesis deficits during lactation

    PMID:19356628

    Open questions at the time
    • Molecular mechanism not addressed in this study
    • Restricted to mammary phenotype readouts
  6. 2011 Medium

    Identified carbohydrate-responsive transcriptional control of Thrsp, linking diet to its expression via ChREBP and histone acetylation.

    Evidence ChIP for ChREBP binding and H3/H4 acetylation at the Thrsp locus in rat jejunum with resistant starch feeding

    PMID:21244091

    Open questions at the time
    • Single tissue and dietary intervention
    • Functional consequence on lipogenesis not directly measured
  7. 2013 High

    Resolved a direct biochemical mechanism: the Spot14/Mig12 heterocomplex inhibits ACC2 by blocking polymerization and carboxylase activity.

    Evidence AFM topography and enzymatic assays with purified recombinant Spot14/Mig12 and human ACC2

    PMID:24277613

    Open questions at the time
    • In vivo relevance of the heterocomplex not demonstrated
    • Stoichiometry/structure of full complex incompletely defined
  8. 2014 High

    Established that THRSP directly enhances FASN activity and medium-chain fatty acid output, defining its second enzymatic regulatory target.

    Evidence In vitro reconstitution with recombinant FASN plus purified Spot14 and add-back rescue in Spot14-null lysates with 13C product quantification

    PMID:24771867

    Open questions at the time
    • Structural basis of FASN activation unknown
    • Whether FASN and ACC2 regulation occur simultaneously unresolved
  9. 2016 Medium

    Connected THRSP to a broader lipogenic gene program in mammary cells, showing it drives medium-chain fatty acid and triacylglycerol synthesis.

    Evidence THRSP overexpression in goat mammary epithelial cells with qRT-PCR and lipid content measurement

    PMID:26851858

    Open questions at the time
    • Direct vs indirect effects on gene expression not distinguished
    • No knockout complement
  10. 2018 Medium

    Revealed a striatal role for THRSP in attention and dopamine signaling, beyond its metabolic functions.

    Evidence Striatal-overexpressing transgenic mice with behavioral testing, expression profiling, and methylphenidate rescue

    PMID:30138648

    Open questions at the time
    • Molecular link between THRSP and dopamine genes unknown
    • Overexpression model may not reflect endogenous role
  11. 2021 Medium

    Extended THRSP function to tumor biology, placing it as a suppressor of EMT in hepatocellular carcinoma.

    Evidence Lentiviral overexpression/shRNA in HCC lines, migration/invasion assays, ERK/ZEB1 western blots, and xenografts

    PMID:34093825

    Open questions at the time
    • ERK/ZEB1 placement is correlative
    • Connection to lipogenic activity not established
  12. 2022 High

    Defined THRSP as an insulin/PI3K-induced regulator of adipocyte mitochondrial function and sphingolipid metabolism in humans.

    Evidence siRNA silencing in SGBS adipocytes with Seahorse respiration, oxidation assays, lipidomics, transcriptomics, and in vivo insulin clamp

    PMID:35715726

    Open questions at the time
    • Direct molecular targets in mitochondria not identified
    • Mechanism linking THRSP to hexosylceramide unknown
  13. 2025 Low

    Showed cell-type-specific transcriptional control of thermogenic and lipogenic programs by Thrsp across adipocyte subtypes.

    Evidence siRNA silencing and T3 treatment in brown, beige, and white adipocyte cell lines with qRT-PCR

    PMID:40317955

    Open questions at the time
    • Gene-expression-only readouts without protein or biochemical validation
    • Mechanism of Mid1ip1 induction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How THRSP coordinates its direct enzymatic regulation of FASN and ACC2 with its diverse downstream roles in mitochondrial, sphingolipid, neuronal, and dopaminergic pathways remains unresolved.
  • No structural model of THRSP bound to FASN or ACC2
  • Mechanism connecting lipogenic activity to neural and dopamine phenotypes unknown
  • Whether THRSP functions enzymatically or solely as a regulatory adaptor in vivo unsettled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-1430728 Metabolism 5
Partners
ACC2FASNMID1IP1
Complex memberships
Spot14/Mig12 heterocomplex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 Spot14 (THRSP) directly enhances FASN catalytic activity: recombinant FASN catalysis increased 1.4-fold and C14:0 yield was enhanced 4-fold in vitro upon addition of purified Spot14; add-back of Spot14 to Spot14-null cytosolic lysates partially restored native FASN activity that was 1.6-fold lower than controls. In vitro reconstitution assay using recombinant FASN with purified Spot14, and crude cytosolic lysate activity assays with 13C fatty acid product quantification Journal of lipid research High 24771867
2013 The Spot14/Mig12 heterocomplex binds purified human ACC2, sequesters its polymerization (blocking citrate-induced filamentous polymer nucleation), and restrains its enzymatic (carboxylase) activity; the oligo-heterocomplex form only partially inhibited, identifying the full heterocomplex as the designated inhibitor. Atomic force microscopy nanoscale protein topography mapping of protein-protein interactions between purified recombinant Spot14/Mig12 and ACC2; functional enzymatic activity assays Journal of molecular recognition : JMR High 24277613
2009 Thrsp null mice exhibit marked deficiencies in de novo lipogenesis specifically in the lactating mammary gland, establishing a required role for Thrsp in mammary gland lipogenesis in vivo. Thrsp knockout mouse (Thrsp(tm1cnm)) phenotypic analysis including body composition and glucose tolerance measurements Molecular and cellular endocrinology High 19356628
2022 In human adipocytes, THRSP is induced by insulin in a PI3K-dependent manner (both mRNA and protein); THRSP silencing impairs mitochondrial respiration and fatty acid oxidation, and decreases hexosylceramide concentrations, placing THRSP upstream of mitochondrial function and sphingolipid metabolism in adipocytes. siRNA silencing in SGBS adipocytes, Seahorse mitochondrial respiration assay, radiolabeled oleate/glucose oxidation and uptake, lipidomic analysis, transcriptomic analysis; in vivo euglycemic insulin clamp with adipose biopsies Molecular medicine (Cambridge, Mass.) High 35715726
2011 ChREBP (carbohydrate response element binding protein) binds the Thrsp gene promoter in rat jejunum, and feeding resistant starch reduces both ChREBP binding and acetylation of histones H3 and H4 at the Thrsp gene, mechanistically linking these epigenetic/transcriptional events to reduced Thrsp expression. Chromatin immunoprecipitation (ChIP) for ChREBP binding and histone acetylation at the Thrsp gene locus; qRT-PCR and western blot for mRNA/protein Journal of agricultural and food chemistry Medium 21244091
2000 NF-Y transcription factor binds the inverted CCAAT-element at position -100 of the rat Spot14 promoter and is required for basal promoter activity, as demonstrated by EMSA and in vitro transcription/translation. Electrophoretic mobility shift assay (EMSA) and in vitro transcription/translation Bioscience, biotechnology, and biochemistry Medium 10830504
2021 THRSP knockdown in HCC cells increases cell growth, migration, and invasion, while THRSP overexpression suppresses tumorigenesis in vivo and in vitro; mechanistically, THRSP inhibits epithelial-to-mesenchymal transition through the ERK/ZEB1 signaling pathway. Lentiviral overexpression and shRNA knockdown in HCC cell lines; transwell and wound healing migration/invasion assays; western blot for ERK and ZEB1; in vivo xenograft Journal of Cancer Medium 34093825
2001 THRP (THRSP) mRNA expression is specifically upregulated during the early (but not late) phase of LTP in rat dentate gyrus; antisense oligonucleotide knockdown of THRP before (but not after) tetanic stimulation prevented LTP induction, and NMDA receptor blockade prevented both LTP and THRP induction, placing THRP downstream of NMDA receptor activation and in the early phase of LTP. PCR differential display, quantitative RT-PCR, in situ hybridization, THRP antisense oligonucleotide treatment, MK801 NMDA receptor blockade, electrophysiological LTP recording in vivo Hippocampus Medium 11811657
2003 Exogenous THRP (THRSP) expression in PC12 neuronal cells induces cell death (predominantly necrosis) and cell cycle arrest; T3 (thyroid hormone) treatment of PC12 cells induces THRP mRNA in a dose-dependent manner and reduces cell number, suggesting THRP mediates TH-induced cytotoxicity. Co-expression with wild-type or kinase-dead c-Abl did not alter THRP-induced cell death. Transfection of THRP expression construct in PC12 cells; TUNEL, propidium iodide/Hoechst staining; 3H-thymidine incorporation; qRT-PCR for THRP mRNA Experimental brain research Medium 12698219
2004 Exogenous THRP (THRSP) expression in primary embryonic rat neurons causes increased cell death; T3 treatment induces THRP mRNA and reduces neuronal cell number, establishing THRP as a mediator of thyroid hormone-induced neuronal cytotoxicity. Co-transfection with wild-type c-Abl did not alter THRP's effect on neuronal survival. Transfection of THRP expression construct in primary rat embryonic neurons; propidium iodide staining; LDH release assay; G418 selection survival assay; qRT-PCR Experimental brain research Medium 15490139
2016 Overexpression of THRSP in goat mammary epithelial cells upregulates FASN, SCD1, DGAT2, and GPAM expression, and increases triacylglycerol concentration and concentrations of C12:0 and C14:0 (medium-chain fatty acids), while downregulating CD36 and having no effect on ACACA or SREBF1. Overexpression of THRSP in primary goat mammary epithelial cells; qRT-PCR for lipogenic gene expression; triglyceride and fatty acid content measurement Journal of dairy science Medium 26851858
2018 THRSP overexpression specifically in the striatum of mice leads to an inattentive phenotype (impaired novel-object recognition and Y-maze performance) without hyperactivity or impulsivity, and is accompanied by upregulation of dopamine transporter, tyrosine hydroxylase, and dopamine D1 and D2 receptor gene expression; methylphenidate normalized attention deficits and dopamine-related gene expression. Transgenic THRSP overexpressing mice; behavioral tests (novel-object recognition, Y-maze, open-field, cliff-avoidance, delay-discounting); qRT-PCR; western blot; methylphenidate pharmacological rescue Neuroscience Medium 30138648
2025 Thrsp (Spot-14) silencing in brown/beige adipocytes upregulates Mid1ip1 (Spot-14R) expression and reduces thermogenic gene expression in brown and beige but not white adipocytes; Thrsp expression is increased by thyroid hormone T3 in brown/beige but decreased in white adipocytes, demonstrating cell-type-specific transcriptional regulation of metabolic and thermogenic pathways. siRNA silencing of Thrsp in EB5 (brown), EB7 (beige), and F442A (white) adipocyte cell lines; qRT-PCR for lipogenic and thermogenic gene expression; T3 treatment FEBS letters Low 40317955
2024 THRSP silencing in mouse mesenchymal stem cells reduces lipid droplet formation and downregulates key adipogenesis regulators (LPL, FABP4, PLIN1, CIDEC) and ER stress marker ATF6, as well as SCD1, LIPE, DGAT1, and AGPAT2, implicating THRSP in ER stress and PPAR signaling pathways that regulate lipid synthesis. THRSP gene silencing in mouse mesenchymal stem cells; transcriptomic and proteomic analysis; lipid droplet staining; RT-qPCR validation Genes Low 39766829
2021 miR-195 directly targets the 3' UTR of THRSP mRNA in buffalo adipocytes (validated by dual-luciferase reporter assay), reducing THRSP expression and inhibiting lipid accumulation, placing THRSP as a downstream effector of miR-195 in adipocyte lipid metabolism. Dual-luciferase reporter gene assay with miR-195 and THRSP 3' UTR; miR-195 overexpression in primary adipocytes; lipid accumulation measurement Frontiers in genetics Low 35003205

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1984 Activation of brain calcineurin towards proteins containing Thr(P) and Ser(P) by Ca2+, calmodulin, Mg2+ and transition metal ions. European journal of biochemistry 40 6092074
2014 Thyroid hormone responsive protein Spot14 enhances catalysis of fatty acid synthase in lactating mammary epithelium. Journal of lipid research 38 24771867
2009 The Thrsp null mouse (Thrsp(tm1cnm)) and diet-induced obesity. Molecular and cellular endocrinology 38 19356628
1992 The comparative efficiencies of the Ser(P)-, Thr(P)- and Tyr(P)-residues as specificity determinants for casein kinase-1. Biochemical and biophysical research communications 38 1540189
2009 Conjugated linoleic acid (CLA) inhibits expression of the Spot 14 (THRSP) and fatty acid synthase genes and impairs the growth of human breast cancer and liposarcoma cells. Nutrition and cancer 37 19116881
2016 Thyroid hormone responsive (THRSP) promotes the synthesis of medium-chain fatty acids in goat mammary epithelial cells. Journal of dairy science 33 26851858
2006 Expression of "Spot 14" (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker. Breast cancer research and treatment 31 16552628
2017 Increased expression of thyroid hormone responsive protein (THRSP) is the result but not the cause of higher intramuscular fat content in cattle. International journal of biological sciences 28 28539828
2018 Overexpression of the Thyroid Hormone-Responsive (THRSP) Gene in the Striatum Leads to the Development of Inattentive-like Phenotype in Mice. Neuroscience 27 30138648
2014 SPOT14-positive neural stem/progenitor cells in the hippocampus respond dynamically to neurogenic regulators. Stem cell reports 25 25418721
2013 Spot14/Mig12 heterocomplex sequesters polymerization and restrains catalytic function of human acetyl-CoA carboxylase 2. Journal of molecular recognition : JMR 22 24277613
2023 Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model. Communications biology 18 36646879
2001 mRNA differential display identification of thyroid hormone-responsive protein (THRP) gene in association with early phase of long-term potentiation. Hippocampus 18 11811657
1998 Age-related changes in thyroid hormone responsive protein (THRP) expression in cerebral tissue of rats. Brain research 16 9630690
2022 Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes. Molecular medicine (Cambridge, Mass.) 15 35715726
2021 Downregulation of THRSP Promotes Hepatocellular Carcinoma Progression by Triggering ZEB1 Transcription in an ERK-dependent Manner. Journal of Cancer 13 34093825
2006 Molecular cloning and expression of the duplicated thyroid hormone responsive spot 14 (THRSP) genes in ducks. Poultry science 10 17012164
2020 Polymorphisms in 5' proximal regulating region of THRSP gene are associated with fat production in pigs. 3 Biotech 9 32509500
2016 Spot14/Spot14R expression may be involved in MSC adipogenic differentiation in patients with adolescent idiopathic scoliosis. Molecular medicine reports 9 27082501
2007 Multifactorial regulation of daily rhythms in expression of the metabolically responsive gene spot14 in the mouse liver. Journal of biological rhythms 9 17660449
2021 Identification and Functional Verification Reveals that miR-195 Inhibiting THRSP to Affect Fat Deposition in Xinyang Buffalo. Frontiers in genetics 8 35003205
2011 Feeding rats dietary resistant starch reduces both the binding of ChREBP and the acetylation of histones on the Thrsp gene in the jejunum. Journal of agricultural and food chemistry 8 21244091
2004 Thyroid hormone responsive protein (THRP) mediates thyroid hormone-induced cytotoxicity in primary neuronal cultures. Experimental brain research 8 15490139
2003 Effect of thyroid hormone responsive protein (THRP) expression on PC12 cell survival. Experimental brain research 8 12698219
2024 Integrative Transcriptomics and Proteomics Analysis Reveals THRSP's Role in Lipid Metabolism. Genes 6 39766829
1991 Production of rat Spot14 protein in Escherichia coli. Gene 6 2022333
2021 Association between THRSP Gene Polymorphism and Fatty Acid Composition in Milk of Dairy Cows. Animals : an open access journal from MDPI 5 33923760
2024 Genome assembly of wisent (Bison bonasus) uncovers a deletion that likely inactivates the THRSP gene. Communications biology 4 39604663
2023 Thrsp Gene and the ADHD Predominantly Inattentive Presentation. ACS chemical neuroscience 4 36716294
2000 Dependence of rat spot14 promoter activity on NF-Y binding to the inverted CCAAT-element at -100. Bioscience, biotechnology, and biochemistry 2 10830504
2025 Unraveling Predominantly Inattentive ADHD (ADHD-PI): Insights from Proteomic Analysis of the Striatum of Thyroid Hormone-Responsive Protein (THRSP)-Overexpressing Mice. Molecular neurobiology 1 40493342
2010 The thyroid hormone responsive protein (THRP) has a critical role in the embryogenesis of Xenopus laevis. Neuroscience letters 1 21095221
2025 Spot-14 and its paralog Spot-14R regulate expression of metabolic and thermogenic pathway genes in murine brown and beige adipocytes. FEBS letters 0 40317955
2009 [Progresses on thyroid hormone responsive spot 14 (THRSP) gene in chickens and ducks]. Yi chuan = Hereditas 0 19273419

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