Affinage

HMGCR

3-hydroxy-3-methylglutaryl-coenzyme A reductase · UniProt P04035

Length
888 aa
Mass
97.5 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HMGCR is the rate-limiting, ER-resident enzyme of the mevalonate pathway, and its activity is gated by an unusually dense network of transcriptional, splicing, and post-translational controls that match cholesterol and isoprenoid output to cellular demand (PMID:31455613, PMID:28342963). Transcriptionally, HMGCR is induced by SREBP-2 acting on two closely spaced sterol-regulatory elements in its promoter, but only when SREBP-2 levels are very high, a threshold that favors uptake of exogenous LDL cholesterol over maximal de novo synthesis (PMID:28342963, PMID:39627481). Output is tuned post-transcriptionally by allele-dependent skipping of exon 13 at rs3846662, governed by HNRNPA1, which yields an enzymatically inactive isoform (PMID:24001602, PMID:18802019), and by 3'-UTR-binding factors including hnRNPR that destabilize HMGCR mRNA (PMID:34258925). Protein stability is the principal feedback node: endogenous C4-dimethylated sterols, lanosterol foremost, trigger ubiquitin-dependent degradation that requires UBXD8 for ER dislocation to the proteasome (PMID:31455613, PMID:28882874), while in the fed state mTORC1 phosphorylates the deubiquitylase USP20 to stabilize HMGCR and rescue metabolic phenotypes via the degradation-resistant K248R mutant (PMID:33177714). The enzyme's principal output, geranylgeranyl pyrophosphate, sustains prenylation of Rho-family GTPases such as Cdc42 and Rac1, maintaining vascular stability and restraining NLRP3 inflammasome activation (PMID:23206891, PMID:39012939), and in Drosophila the same isoprenoid branch geranylates Ggamma1 to control long-range germ cell attraction and Hedgehog ligand release (PMID:19132091, PMID:24068944). Bi-allelic loss-of-function variants in HMGCR cause autosomal-recessive progressive limb-girdle muscular dystrophy that reflects deficient mevalonate flux and is rescued by oral mevalonolactone (PMID:37167966, PMID:36745799).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2008 High

    Established that a common intronic variant controls HMGCR output not by changing total expression alone but by directing production of a catalytically dead splice isoform, defining splicing as a tunable lever on enzyme activity.

    Evidence Minigene splicing assay and functional complementation of exon-13-deleted variant in HMGCR-deficient UT-2 cells with GWAS replication

    PMID:18802019

    Open questions at the time
    • Did not identify the trans-acting splicing factor
    • Did not quantify the isoform's contribution to systemic cholesterol
  2. 2008 Medium

    Linked HMGCR expression to circadian timing, showing its phase tracks sterol-synthesis rhythms under CREM control, though indirectly.

    Evidence Circadian profiling in Crem-knockout mouse liver with GC-MS sterol measurement and promoter-reporter assays

    PMID:18775413

    Open questions at the time
    • The intermediary linking CREM to Hmgcr is unidentified
    • Promoter reporters showed no direct CREM action
  3. 2013 High

    Identified HNRNPA1 as the allele-specific trans factor that drives exon-13 skipping at rs3846662, mechanistically connecting the SNP to reduced enzyme activity and altered LDL handling.

    Evidence rs3846662 binding assay, HNRNPA1 overexpression in hepatoma cells, enzyme activity and LDL-C uptake assays with clinical statin-response correlation

    PMID:24001602

    Open questions at the time
    • Did not resolve how sterol status alters HNRNPA1 activity
    • Tissue-specificity of the splicing effect not mapped
  4. 2017 High

    Defined the transcriptional threshold logic of HMGCR induction, showing its two SREs respond only to very high SREBP-2, prioritizing exogenous cholesterol uptake over de novo synthesis.

    Evidence Luciferase reporter mutant libraries, EMSA, and ChIP-PCR on the human HMGCR promoter

    PMID:28342963

    Open questions at the time
    • Did not address combinatorial input from other promoter factors in vivo
    • Did not connect threshold to physiological SREBP-2 ranges
  5. 2017 High

    Identified UBXD8 as the dislocation factor required to extract ubiquitylated HMGCR from the ER membrane, defining a discrete step in sterol-accelerated degradation.

    Evidence Unbiased haploid genetic screen on endogenous HMGCR-mNeon cells with UBX-domain mutagenesis and ER dislocation assays

    PMID:28882874

    Open questions at the time
    • Did not identify the upstream E3 ligase coupling sterol sensing to HMGCR ubiquitination
    • Structural basis of dislocation unresolved
  6. 2019 High

    Pinpointed lanosterol and other C4-dimethylated sterols as the bona fide endogenous signals that selectively accelerate HMGCR turnover, separating degradation control from SREBP-2 cleavage control.

    Evidence CRISPR deletion of mevalonate-pathway enzymes in HeLa cells with lipidomics and protein-level readouts

    PMID:31455613

    Open questions at the time
    • The direct sterol sensor for HMGCR degradation not isolated
    • Quantitative thresholds for in vivo regulation unknown
  7. 2020 High

    Closed the fed-state arm of HMGCR control by showing mTORC1-phosphorylated USP20 stabilizes HMGCR, with degradation-resistant HMGCR(K248R) reversing metabolic phenotypes, integrating nutrient signaling with cholesterol synthesis.

    Evidence Liver-specific Usp20 knockout, USP20(S132A/S134A) knock-in mice, phospho-site mapping, Co-IP, and HMGCR(K248R) rescue

    PMID:33177714

    Open questions at the time
    • How USP20 recruitment integrates with the UBXD8/sterol degradation arm not resolved
    • Relevant E3 ligase counteracted by USP20 not defined in this study
  8. 2009 High

    Placed Hmgcr upstream of Ggamma1 geranylation in Drosophila, establishing that isoprenoid output, not sterol synthesis per se, generates a germ cell attractant and supports Hedgehog ligand release.

    Evidence Genetic epistasis with trans-heterozygous mutant combinations and dominant-negative non-geranylatable Ggamma1

    PMID:19132091

    Open questions at the time
    • The identity of the secreted attractant remained unknown
    • Mammalian conservation of this branch not tested
  9. 2012 High

    Demonstrated that HMGCR-derived GGPP is required for vascular integrity via prenylation of Rho GTPases, providing a metabolite-rescue causal link in vivo.

    Evidence Pharmacological and genetic HMGCR inhibition in zebrafish with GGPP rescue, GGTase I morpholino knockdown, and endothelial Cdc42 analysis

    PMID:23206891

    Open questions at the time
    • Did not resolve which prenylated GTPase is rate-limiting for vessel stability
    • Did not map effector signaling downstream of Cdc42
  10. 2019 Medium

    Refined the Drosophila germ cell model by showing Hmgcr-driven attraction acts at long range and dose-dependently and is independent of both Hedgehog and Wunens, revising the earlier attractant assignment.

    Evidence Quantitative germ cell migration assays with hmgcr, wunens, and hh genetic epistasis

    PMID:31719159

    Open questions at the time
    • The molecular nature of the attractant remains unidentified
    • Single-lab finding contradicting prior model
  11. 2014 Medium

    Showed HMGCR can drive tumor growth via Hedgehog/Gli1 signaling in gastric cancer, extending its role beyond metabolism to oncogenic signaling.

    Evidence HMGCR overexpression and shRNA knockdown with tumorigenesis assays and Gli1 pathway analysis

    PMID:27085483

    Open questions at the time
    • The metabolite linking HMGCR to Gli1 activation not defined
    • Single-lab and cancer-type specific
  12. 2021 Medium

    Connected HMGCR-derived GGPP supply to innate immunity, showing that reduced prenylation of Rac1 unleashes NLRP3 inflammasome activation through IQGAP1 binding.

    Evidence GGPP and Rac1 prenylation measurement, IQGAP1 Co-IP, and IL-1beta assays in patient monocytes

    PMID:39012939

    Open questions at the time
    • Direct physiological triggers of HMGCR constraint not generalized beyond glucose-oxygen deprivation
    • Single-lab finding
  13. 2023 High

    Established HMGCR as a Mendelian disease gene by showing bi-allelic loss-of-function variants cause autosomal-recessive limb-girdle muscular dystrophy through reduced enzyme activity and stability, with mevalonolactone providing therapeutic rescue.

    Evidence Exome sequencing across families, enzyme activity and stability assays on patient variants, molecular modeling, and mevalonolactone treatment in patient and statin-myopathy mouse model

    PMID:36745799 PMID:37167966

    Open questions at the time
    • Why muscle is selectively vulnerable to mevalonate deficiency not fully explained
    • Long-term efficacy of mevalonolactone not established
  14. 2022 Medium

    Catalogued additional ubiquitin-system and RNA-binding regulators (SIAH1, BRCC36, hnRNPR, ZFAS1/U2AF2) that fine-tune HMGCR levels in disease contexts, broadening the regulatory map.

    Evidence Co-IP/ubiquitination assays, RIP and RNA pulldown, and knockdown/knockout with lipid and tumor readouts across cancer models

    PMID:34258925 PMID:35846429 PMID:37062828 PMID:38178583

    Open questions at the time
    • These regulators are largely demonstrated in single labs and specific cancer cells
    • Integration with the canonical sterol-degradation machinery not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct sterol sensor and the full E3 ligase set that couple lanosterol detection to HMGCR ubiquitination, and the molecular identity of the Drosophila Hmgcr-dependent germ cell attractant, remain unresolved.
  • No isolated direct sterol receptor for degradation
  • Attractant downstream of Hmgcr unidentified
  • Relationship among USP20, SIAH1, BRCC36, and UBXD8 in vivo unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016740 transferase activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 2
Partners
BRCC36HNRNPA1HNRNPRHSP90SIAH1U2AF2UBXD8USP20

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 The deubiquitylase USP20 stabilizes HMGCR in the fed state by antagonizing its ubiquitin-dependent degradation. mTORC1, activated by post-prandial insulin and glucose, phosphorylates USP20 at S132 and S134, recruiting it to the HMGCR complex. Feeding-induced HMGCR stabilization is abolished in liver-specific Usp20-knockout and USP20(S132A/S134A) knock-in mice, and metabolic phenotypes are reversed by constitutively stable HMGCR(K248R). Genetic mouse models (liver-specific knockout, knock-in), in vivo feeding experiments, phosphorylation mapping, Co-IP, functional rescue with HMGCR(K248R) Nature High 33177714
2019 Among endogenous sterol intermediates of the mevalonate pathway, C4-dimethylated sterols (lanosterol, 24,25-dihydrolanosterol, follicular fluid meiosis activating sterol, testis meiosis activating sterol, dihydro-testis meiosis activating sterol) stimulate HMGCR degradation and inhibit SREBP-2 cleavage. Lanosterol specifically and selectively promotes HMGCR degradation without inhibiting SREBP-2 cleavage, establishing it as a bona fide endogenous regulator of HMGCR turnover. CRISPR/Cas9-mediated gene deletion of mevalonate pathway enzymes in HeLa cells expressing mevalonate transporter, lipidomics to measure sterol intermediates, HMGCR protein level assays Journal of lipid research High 31455613
2017 UBXD8 (UBX domain-containing protein 8) is an essential determinant of sterol-stimulated HMGCR degradation. UBXD8 is required for dislocation of ubiquitylated HMGCR from the ER membrane en route to proteasomal degradation, a function dependent on its UBX domain. UBXD8 ablation leads to aberrant cholesterol synthesis due to loss of feedback control. Unbiased haploid mammalian genetic screen using CRISPR/Cas9-tagged endogenous HMGCR-mNeon cells, UBXD8 knockdown/knockout in multiple cell types, UBX-domain mutagenesis, ER dislocation assays Arteriosclerosis, thrombosis, and vascular biology High 28882874
2013 HNRNPA1 regulates HMGCR alternative splicing (exon 13 skipping) in an allele-dependent manner at rs3846662, which alters an HNRNPA1 binding motif. HNRNPA1 overexpression increases the ratio of HMGCR exon-13-skipping transcript, specifically stabilizes that isoform, and diminishes HMGCR enzyme activity while enhancing LDL-C uptake and increasing cellular apolipoprotein B. rs3846662 binding assay for HNRNPA1, sterol depletion/add-back experiments, HNRNPA1 overexpression in hepatoma cell lines, HMGCR enzyme activity assay, LDL-C uptake assay, clinical statin-response correlation Human molecular genetics High 24001602
2008 An intronic SNP in HMGCR (rs3846662) directly modulates alternative splicing of exon 13; the minor allele is associated with up to 2.2-fold lower expression of the alternatively spliced HMGCR transcript lacking exon 13. The exon-13-deleted splice variant cannot restore HMGCR activity when expressed in HMGCR-deficient UT-2 cells, indicating it encodes a non-functional enzyme. Minigene transfection assay, in vitro splicing in human lymphoblastoid cells, functional complementation in HMGCR-deficient UT-2 cells, GWAS with replication Arteriosclerosis, thrombosis, and vascular biology High 18802019
2017 Two sterol-regulatory elements (SREs) in close proximity exist in the human HMGCR promoter, along with one NF-Y binding site. HMGCR transcription is highly activated only when SREBP-2 levels are very high, in contrast to LDLR, ensuring preferential uptake of exogenous cholesterol before de novo synthesis is maximally induced. Luciferase reporter assays with SRE/NF-Y/Sp1 site mutant libraries, electrophoretic mobility shift assay (EMSA), ChIP-PCR Biochimica et biophysica acta. Molecular and cell biology of lipids High 28342963
2024 BRCC36 deubiquitinates HMGCR in a DUB-activity-dependent manner, inhibiting ferroptosis and promoting pyroptosis. HMGCR predominantly localizes to mitochondria during ferroptosis but shifts to the endoplasmic reticulum following pyroptosis induction. Thiolutin, a BRCC36 inhibitor, suppresses the BRCC36–HMGCR interaction. Co-IP, subcellular fractionation/localization (confocal microscopy), DUB activity assays, pharmacological inhibition with thiolutin, in vivo HCC xenograft Advanced science Medium 38178583
2012 In zebrafish, HMGCR pathway activity is required for cerebral-vascular stability via prenylation-dependent signaling. Cerebral hemorrhages induced by pharmacological or genetic HMGCR inhibition are rescued by exogenous geranylgeranyl pyrophosphate (GGPP), and mimicked by morpholino knockdown of GGTase I (geranylgeranyltransferase I β-subunit), implicating protein geranylgeranylation of Rho GTPases (including Cdc42) downstream of HMGCR. Pharmacological HMGCR inhibition (statins), genetic HMGCR knockdown, GGPP rescue supplementation, morpholino knockdown of GGTase I, endothelial Cdc42 expression analysis in zebrafish Developmental biology High 23206891
2009 In Drosophila, the hmgcr-dependent isoprenoid pathway geranylates the G-protein γ-subunit Ggamma1, which is required for efficient release of the Hedgehog ligand from hh-expressing cells and for production of the germ cell attractant by somatic gonadal precursors. Trans-heterozygous combinations between ggamma1, hmgcr, and hh mutations disrupt germ cell migration, placing Ggamma1 downstream of Hmgcr in this pathway. Genetic epistasis (trans-heterozygous mutant combinations), loss- and gain-of-function ggamma1 experiments, dominant-negative non-geranylatable Ggamma1, ectopic hmgcr expression PLoS genetics High 19132091
2013 In Drosophila, the hedgehog pathway gene shifted (shf) cooperates with the hmgcr-dependent isoprenoid pathway to generate the germ cell attractant and to enhance the potency and long-range transmission of Hh from somatic gonadal precursors. The potentiation of Hh by ectopic hmgcr expression depends on cholesterol modification of Hh. Loss- and gain-of-function genetics (shf, hmgcr, hh), ectopic expression in nervous system, epistasis analysis, in vivo germ cell migration assay PLoS genetics Medium 24068944
2019 In Drosophila, the attractive signal for germ cell migration downstream of Hmgcr is cell-contact independent and acts at long range in a dose-dependent manner. This Hmgcr-mediated attraction does not require Wunens and operates independently of Hedgehog signaling, contradicting earlier proposals that Hh is the germ cell attractant downstream of Hmgcr. Quantitative germ cell migration assays, genetic epistasis (hmgcr, wunens, hh), tissue-specific expression experiments in Drosophila Journal of cell science Medium 31719159
2007 In Drosophila, HMGCR expression in the corpus allatum (the gland where juvenile hormone is synthesized) is controlled by the insulin receptor (InR). Targeted RNAi against InR in the corpus allatum blocks both InR and HMGCR expression, while RNAi against HMGCR blocks only HMGCR; both disruptions cause loss of sexual dimorphism in locomotor activity and produce dwarf flies, placing HMGCR downstream of insulin signaling in JH biosynthesis. Tissue-specific RNAi (GAL4/UAS system) in Drosophila corpus allatum, locomotor activity assays, body size measurements PloS one Medium 17264888
2021 In Tregs, loss of AMPKα1 promotes expression of HMGCR and glycolysis. AMPK activates p38 MAPK, which phosphorylates GSK-3β to inhibit PD-1 expression; mechanistically, HMGCR upregulation (downstream of AMPK loss) leads to elevated PD-1. Thus, AMPK suppresses PD-1 in Tregs via the HMGCR/p38 MAPK/GSK-3β signaling pathway. AMPKα1 conditional knockout in Tregs (AMPKα1fl/fl Foxp3YFP-Cre mice), western blotting, immunoprecipitation, immunofluorescence, flow cytometry Molecular cancer Medium 34649584
2018 HSP90 physically interacts with HMGCR (co-immunoprecipitation) and regulates HMGCR protein levels by inhibiting its proteasomal degradation. Lovastatin (HMGCR inhibitor) impairs HSP90-dependent oncogenic functions (growth, migration, colony formation) in hepatocellular carcinoma cells. Immunoprecipitation, western blotting, lovastatin pharmacological inhibition, cell growth/migration assays Molecular medicine reports Low 30483734
2021 Under glucose-oxygen deprivation in human monocytes, HMGCR function is constrained, reducing GGPP synthesis; this decreases prenylation of the small GTPase Rac1, leading to increased binding of non-prenylated Rac1 to IQGAP1 and enhanced NLRP3 inflammasome activation and IL-1β release. GGPP measurement, Rac1 prenylation assay, IQGAP1 co-IP, NLRP3 inflammasome activation assay, IL-1β ELISA, primary patient monocytes (mevalonate kinase deficiency, Muckle-Wells syndrome) vs. controls Science signaling Medium 39012939
2023 Bi-allelic loss-of-function (amorphic) variants in HMGCR cause autosomal-recessive progressive limb-girdle muscular dystrophy. Protein activity studies of three variants (p.Asp623Asn, p.Tyr792Cys, p.Arg443Gln) confirmed decreased enzymatic activity and reduced protein stability, and molecular modeling showed the variants destabilize the protein and affect oligomerization. Exome sequencing, HMGCR enzyme activity assays, protein stability assays, molecular modeling, clinical phenotyping American journal of human genetics High 37167966
2023 A homozygous missense loss-of-function mutation in HMGCR causes late-onset severe progressive limb-girdle muscular disease in humans. Oral mevalonolactone (the downstream mevalonate pathway product) is effective in treating this hereditary HMGCR myopathy in a patient and resolves statin-induced myopathy in mice, demonstrating that the myopathy results from deficient mevalonate pathway flux. Homozygosity mapping, whole exome sequencing, biochemical and biophysical functional analysis (confocal microscopy), biochemical synthesis of mevalonolactone, mouse statin myopathy model, human patient treatment Proceedings of the National Academy of Sciences of the United States of America High 36745799
2022 SIAH1, an E3 ubiquitin ligase, ubiquitinates HMGCR and thereby reduces HMGCR protein levels, inhibiting cholesterol synthesis and efflux protein activity in lung cancer cells. SIAH1 overexpression or HMGCR knockdown retards tumor growth and enhances cisplatin efficacy in vivo. Co-IP/ubiquitination assay, SIAH1 overexpression, HMGCR knockdown, xenograft mouse model, cholesterol measurement Cancer cell international Medium 37062828
2021 HMGCR inhibition (by statins or siRNA) in renal cell carcinoma leads to increased HSP90 expression, which stabilizes the glycolytic enzyme PKM2, thereby accelerating glycolysis and tumor growth. Suppressing glycolysis (via PKM2 inhibitor Shikonin) reverses the HMGCR inhibition-induced tumor growth acceleration. HMGCR siRNA knockdown, statin treatment, HSP90 expression measurement, PKM2 protein level and activity assays, RCC xenograft mouse model, Shikonin rescue PLoS biology Medium 33905408
2021 hnRNPR binds directly to the 3′-UTR of HMGCR mRNA via its RNA recognition motif (RRM), reducing HMGCR mRNA stability and translation, thereby decreasing HMGCR protein levels and neuronal cholesterol. HMGCR overexpression reverses the decrease in cholesterol caused by hnRNPR overexpression. RNA immunoprecipitation (RIP), luciferase reporter assay (3′-UTR), hnRNPR knockdown and overexpression in N2a and MN1 cells, cholesterol measurement, HMGCR rescue overexpression Journal of integrative neuroscience Medium 34258925
2022 lncRNA ZFAS1 stabilizes HMGCR mRNA by binding the RNA-binding protein U2AF2; U2AF2 in turn binds HMGCR mRNA and prevents its degradation, increasing HMGCR expression and promoting lipid accumulation in pancreatic carcinoma cells. RNA pulldown, RIP assay (ZFAS1–U2AF2 and U2AF2–HMGCR mRNA interactions), ZFAS1 gene knockout, U2AF2 and HMGCR knockdown, lipid content measurement Journal of immunology research Medium 35846429
2019 Auranofin (anticancer gold compound) directly inhibits HMGCR enzymatic activity at micromolar IC50 levels. The auranofin-induced cancer cell death is partially reversed by downstream mevalonate pathway products (mevalonolactone or GGPP), indicating HMGCR inhibition contributes to its anticancer mechanism. In vitro HMGCR enzyme activity inhibition assay, mevalonolactone and GGPP rescue experiments, subcellular fractionation proteomics Metallomics Medium 31631207
2008 CREM isoforms regulate the circadian expression of cholesterogenic genes in mouse liver; Hmgcr shows a phase advance (from CT20 to CT12) in Crem-knockout livers, and this corresponds to a phase advance in the lathosterol/cholesterol ratio. CREMtau and ICER have little effect on the Hmgcr proximal promoter, suggesting the circadian regulation of Hmgcr by CREM is indirect. Circadian expression profiling in Crem-knockout mice, GC-MS for sterol intermediates, promoter-reporter assays with CREMtau and ICER overexpression Biochemical and biophysical research communications Medium 18775413
2012 In weaning piglets, maternal low-protein diet induces HMGCR promoter hypomethylation, decreased histone H3 methylation (H3K9me1, H3K27me3) and increased H3 acetylation, which is associated with increased HMGCR mRNA expression and enzyme activity in the liver. Bisulfite sequencing/methylation analysis of HMGCR promoter, histone modification analysis (ChIP), HMGCR mRNA (qPCR), HMGCR enzyme activity assay in piglet liver The Journal of nutritional biochemistry Medium 22444501
2022 The S1P-induced proteolytic activation of SREBPs drives HMGCR expression in erythroblasts subjected to shear stress during differentiation; inhibition of S1P-mediated SREBP cleavage abolishes HMGCR upregulation and leads to erythroblast loss in dynamic culture, equivalent to lovastatin treatment. Shear stress experiments on primary human erythroblasts, S1P inhibition, lovastatin treatment, gene expression profiling, HMGCR protein quantification, osmotic resistance assay Scientific reports Medium 39627481
2014 HMGCR (the rate-limiting enzyme of the mevalonate pathway) promotes gastric cancer cell growth and migration; knockdown inhibits growth, migration, and tumorigenesis. Mechanistically, HMGCR activates Hedgehog/Gli1 signaling and upregulates Gli1 target genes. HMGCR overexpression and shRNA knockdown in gastric cancer cells, cell growth/migration assays, in vivo tumorigenesis, Hedgehog/Gli1 pathway analysis Gene Medium 27085483
2024 In anti-HMGCR immune-mediated necrotizing myopathy, in vitro immunostaining on primary myotubes exposed to purified patient-derived anti-HMGCR autoantibodies reproduces the presence of HMGCR protein on altered myofibers, and sarcolemmal complement deposits (classical pathway activation) correlate with fiber necrosis (r=0.4, p=0.004), implicating antibody-mediated complement activation as a pathogenic mechanism. In vitro immunostaining with purified patient autoantibodies on primary myotubes, muscle biopsy immunostaining, correlation analysis of complement deposits and necrosis Neurology Medium 29330311

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). The Journal of biological chemistry 298 23696639
2020 Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis. Nature 219 33177714
2015 MicroRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1. Scientific reports 158 26632252
2018 Necrosis in anti-SRP+ and anti-HMGCR+myopathies: Role of autoantibodies and complement. Neurology 148 29330311
2015 miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR. International journal of molecular medicine 119 25605429
2013 Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle & nerve 112 23519993
2008 Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13. Arteriosclerosis, thrombosis, and vascular biology 110 18802019
2015 Clinical course and treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy. Neurology(R) neuroimmunology & neuroinflammation 97 25866831
2018 Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy. Neurology(R) neuroimmunology & neuroinflammation 87 30588482
2019 Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing. Journal of lipid research 85 31455613
2015 Myopathy with anti-HMGCR antibodies: Perimysium and myofiber pathology. Neurology(R) neuroimmunology & neuroinflammation 85 26090508
2016 HMGCR is up-regulated in gastric cancer and promotes the growth and migration of the cancer cells. Gene 81 27085483
2021 AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway. Molecular cancer 79 34649584
2007 Hmgcr in the corpus allatum controls sexual dimorphism of locomotor activity and body size via the insulin pathway in Drosophila. PloS one 77 17264888
2017 New insights into cellular cholesterol acquisition: promoter analysis of human HMGCR and SQLE, two key control enzymes in cholesterol synthesis. Biochimica et biophysica acta. Molecular and cell biology of lipids 75 28342963
2021 Atorvastatin Ester Regulates Lipid Metabolism in Hyperlipidemia Rats via the PPAR-signaling Pathway and HMGCR Expression in the Liver. International journal of molecular sciences 63 34681767
2015 AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver. PloS one 63 25933205
2017 Stromal regulation of prostate cancer cell growth by mevalonate pathway enzymes HMGCS1 and HMGCR. Oncology letters 61 29163687
2013 HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism. Human molecular genetics 55 24001602
2009 The role of HMGCR alternative splicing in statin efficacy. Trends in cardiovascular medicine 51 20005478
2015 HMGCR positively regulated the growth and migration of glioblastoma cells. Gene 50 26432005
2014 A preliminary study of the relationship between promoter methylation of the ABCG1, GALNT2 and HMGCR genes and coronary heart disease. PloS one 50 25084356
2019 Therapeutic targets of hypercholesterolemia: HMGCR and LDLR. Diabetes, metabolic syndrome and obesity : targets and therapy 47 31686875
2020 Statin use, HMGCR expression, and breast cancer survival - The Malmö Diet and Cancer Study. Scientific reports 46 31953433
2012 Maternal low-protein diet causes epigenetic deregulation of HMGCR and CYP7α1 in the liver of weaning piglets. The Journal of nutritional biochemistry 46 22444501
2012 The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway. Developmental biology 45 23206891
2023 Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone. Proceedings of the National Academy of Sciences of the United States of America 44 36745799
2023 Anti-HMGCR immune-mediated necrotising myopathy: Addressing the remaining issues. Autoimmunity reviews 41 37884200
2017 Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis. Acta pharmacologica Sinica 41 28112179
2024 BRCC36 Deubiquitinates HMGCR to Regulate the Interplay Between Ferroptosis and Pyroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 39 38178583
2018 Long noncoding RNA lncARSR promotes hepatic cholesterol biosynthesis via modulating Akt/SREBP-2/HMGCR pathway. Life sciences 38 29678744
2018 Rituximab in the Treatment of Refractory Anti-HMGCR Immune-mediated Necrotizing Myopathy. The Journal of rheumatology 37 30554155
2014 HMGCR is necessary for the tumorigenecity of esophageal squamous cell carcinoma and is regulated by Myc. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 36 24390662
2018 Blood lipid genetic scores, the HMGCR gene and cancer risk: a Mendelian randomization study. International journal of epidemiology 35 29165714
2009 Interaction between HMGCR and ABCA1 cholesterol-related genes modulates Alzheimer's disease risk. Brain research 32 19446537
2019 Bisphenol A induces cholesterol biosynthesis in HepG2 cells via SREBP-2/HMGCR signaling pathway. The Journal of toxicological sciences 31 31270304
2012 Transcriptional and posttranscriptional inhibition of HMGCR and PC biosynthesis by geraniol in 2 Hep-G2 cell proliferation linked pathways. Biochemistry and cell biology = Biochimie et biologie cellulaire 30 23668785
2017 Haploid Mammalian Genetic Screen Identifies UBXD8 as a Key Determinant of HMGCR Degradation and Cholesterol Biosynthesis. Arteriosclerosis, thrombosis, and vascular biology 29 28882874
2008 CREM modulates the circadian expression of CYP51, HMGCR and cholesterogenesis in the liver. Biochemical and biophysical research communications 29 18775413
2023 Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy. American journal of human genetics 28 37167966
2016 Statin-associated autoimmune myopathy: A distinct new IFL pattern can increase the rate of HMGCR antibody detection by clinical laboratories. Autoimmunity reviews 28 27640317
2024 Inhibiting HMGCR represses stemness and metastasis of hepatocellular carcinoma via Hedgehog signaling. Genes & diseases 27 39022130
2010 Functional and association studies on the pig HMGCR gene, a cholesterol-synthesis limiting enzyme. Animal : an international journal of animal bioscience 27 22443876
2016 Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia. Pharmacogenetics and genomics 26 26466344
2022 The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway. Journal of pharmaceutical analysis 25 36820075
2022 Prevention of Anti-HMGCR Immune-Mediated Necrotising Myopathy by C5 Complement Inhibition in a Humanised Mouse Model. Biomedicines 23 36009583
2021 HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma. PLoS biology 23 33905408
2019 YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine. Biomolecules 23 31627466
2018 Statin-naïve anti-HMGCR antibody-mediated necrotizing myopathy in China. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 23 30205933
2009 Ggamma1, a downstream target for the hmgcr-isoprenoid biosynthetic pathway, is required for releasing the Hedgehog ligand and directing germ cell migration. PLoS genetics 23 19132091
2022 Rewiring Lipid Metabolism by Targeting PCSK9 and HMGCR to Treat Liver Cancer. Cancers 21 36612001
2020 NPY stimulates cholesterol synthesis acutely by activating the SREBP2-HMGCR pathway through the Y1 and Y5 receptors in murine hepatocytes. Life sciences 21 32976883
2023 Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas. Nature communications 20 37277330
2022 Perivascular and endomysial macrophages expressing VEGF and CXCL12 promote angiogenesis in anti-HMGCR immune-mediated necrotizing myopathy. Rheumatology (Oxford, England) 20 34864921
2021 Anti-HMGCR myopathy overlaps with dermatomyositis-like rash: a distinct subtype of idiopathic inflammatory myopathy. Journal of neurology 20 34021410
2019 SREBP2 is upregulated in esophageal squamous cell carcinoma and co‑operates with c‑Myc to regulate HMGCR expression. Molecular medicine reports 19 31432128
2023 Chlorogenic acid regulates the expression of NPC1L1 and HMGCR through PXR and SREBP2 signaling pathways and their interactions with HSP90 to maintain cholesterol homeostasis. Phytomedicine : international journal of phytotherapy and phytopharmacology 18 38103317
2021 Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction. Acta pharmacologica Sinica 18 34588618
2013 The hedgehog pathway gene shifted functions together with the hmgcr-dependent isoprenoid biosynthetic pathway to orchestrate germ cell migration. PLoS genetics 18 24068944
2022 CAPRIN2 upregulation by LINC00941 promotes nasopharyngeal carcinoma ferroptosis resistance and metastatic colonization through HMGCR. Frontiers in oncology 17 36276162
2022 lncRNA ZFAS1 Promotes HMGCR mRNA Stabilization via Binding U2AF2 to Modulate Pancreatic Carcinoma Lipometabolism. Journal of immunology research 16 35846429
2018 HSP90 interacts with HMGCR and promotes the progression of hepatocellular carcinoma. Molecular medicine reports 15 30483734
2021 A Possible Role for HMG-CoA Reductase Inhibitors and Its Association with HMGCR Genetic Variation in Parkinson's Disease. International journal of molecular sciences 14 34830081
2020 Anti-HMGCR Antibody-Positive Myopathy Shows Bcl-2-Positive Inflammation and Lymphocytic Accumulations. Journal of neuropathology and experimental neurology 14 32100014
2024 Glucose-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes. Science signaling 13 39012939
2023 Clinical and Radiological Features of Korean Patients With Anti-HMGCR Myopathy. Journal of clinical neurology (Seoul, Korea) 13 36929062
2023 Assessing the Impact of PCSK9 and HMGCR Inhibition on Liver Function: Drug-Target Mendelian Randomization Analyses in Four Ancestries. Cellular and molecular gastroenterology and hepatology 13 37703945
2021 PRL-1 overexpressed placenta-derived mesenchymal stem cells suppress adipogenesis in Graves' ophthalmopathy through SREBP2/HMGCR pathway. Stem cell research & therapy 13 34051850
2021 Concomitant attenuation of HMGCR expression and activity enhances the growth inhibitory effect of atorvastatin on TGF-β-treated epithelial cancer cells. Scientific reports 13 34140545
2014 Developmental processes regulated by the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway: highlights from animal studies. Reproductive toxicology (Elmsford, N.Y.) 13 24732207
2023 SIAH1 ubiquitination-modified HMGCR inhibits lung cancer progression and promotes drug sensitivity through cholesterol synthesis. Cancer cell international 12 37062828
2022 Alpinumisoflavone Exhibits the Therapeutic Effect on Prostate Cancer Cells by Repressing AR and Co-Targeting FASN- and HMGCR-Mediated Lipid and Cholesterol Biosynthesis. Life (Basel, Switzerland) 12 36362924
2018 Protective effect of atorvastatin meditated by HMGCR gene on diabetic rats with atherosclerosis: An in vivo and in vitro study. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 12 29775891
2012 The orphan nuclear receptor Nur77 regulates hepatic cholesterol metabolism through the suppression of LDLR and HMGCR expression. Molecular medicine reports 12 22470048
2022 Identification of HMGCR, PPGARG and prohibitin as potential druggable targets of dihydrotestosterone for treatment against traumatic brain injury using system pharmacology. International immunopharmacology 11 35344815
2022 High-Risk Polymorphisms Associated with the Molecular Function of Human HMGCR Gene Infer the Inhibition of Cholesterol Biosynthesis. BioMed research international 11 35707384
2019 Anticancer auranofin engages 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as a target. Metallomics : integrated biometal science 11 31631207
2017 HMGCR and ApoE mutations may cause different responses to lipid lowering statin therapy. Cellular and molecular biology (Noisy-le-Grand, France) 11 29096742
2024 Betaine supplementation alleviates corticosterone-induced hepatic cholesterol accumulation through epigenetic modulation of HMGCR and CYP7A1 genes in laying hens. Poultry science 10 38232620
2022 The Statin Target Hmgcr Regulates Energy Metabolism and Food Intake through Central Mechanisms. Cells 10 35326421
2011 Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk. Molecular neurodegeneration 10 21867541
2011 Explication of interactions between HMGCR isoform 2 and various statins through In silico modeling and docking. Computers in biology and medicine 10 22177940
2019 cDNA cloning, prokaryotic expression and functional analysis of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in Pogostemon cablin. Protein expression and purification 9 31301429
2015 Association between the Lipid Levels and Single Nucleotide Polymorphisms of ABCA1, APOE and HMGCR Genes in Subjects with Spontaneous Preterm Delivery. PloS one 9 26301579
2024 Absence of Pathogenic Mutations and Strong Association With HLA-DRB1*11:01 in Statin-Naïve Early-Onset Anti-HMGCR Necrotizing Myopathy. Neurology(R) neuroimmunology & neuroinflammation 8 39106428
2021 RNA-binding protein hnRNPR reduces neuronal cholesterol levels by binding to and suppressing HMGCR. Journal of integrative neuroscience 8 34258925
2020 Transthyretin Regulated by linc00657/miR-205-5p Promoted Cholesterol Metabolism by Inducing SREBP2-HMGCR and Inhibiting LXRα-CYP7A1. Archives of medical research 8 32241558
2019 Hmgcr promotes a long-range signal to attract Drosophila germ cells independently of Hedgehog. Journal of cell science 8 31719159
2018 Coexistence of anti-HMGCR and anti-MDA5 identified by an unlabeled immunoprecipitation assay in a chinese patient cohort with myositis. Medicine 8 30461626
2015 Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer's Disease Pathology. Journal of molecular neuroscience : MN 8 26541602
2009 Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome. Fertility and sterility 8 19327767
2025 The incidence of anti-HMGCR immune-mediated necrotizing myopathy: an Australian and UK retrospective multi-site cohort study. Rheumatology (Oxford, England) 7 40347460
2024 LY86 facilitates ox-LDL-induced lipid accumulation in macrophages by upregulating SREBP2/HMGCR expression. BMC cardiovascular disorders 7 38822281
2024 Differentiating erythroblasts adapt to mechanical stimulation by upregulation of cholesterol biosynthesis via S1P/SREBP-induced HMGCR expression. Scientific reports 7 39627481
2021 Rebaudioside A Enhances LDL Cholesterol Uptake in HepG2 Cells via Suppression of HMGCR Expression. Reports of biochemistry & molecular biology 7 34981026
2020 LINC00202 promotes retinoblastoma progression by regulating cell proliferation, apoptosis, and aerobic glycolysis through miR-204-5p/HMGCR axis. Open life sciences 7 33817232
2019 Porcine HMGCR Inhibits Porcine Circovirus Type 2 Infection by Directly Interacting with the Viral Proteins. Viruses 7 31212640
2018 Autoimmune necrotising myopathy and HMGCR antibodies. Practical neurology 7 29439058
2010 The effect of a mutation in the 3-UTR region of the HMGCR gene on cholesterol in Beijing-you chickens. Animal biotechnology 7 20967643
2023 Electroacupuncture regulates hepatic cholesterol synthesis by HMGCR deubiquitination in rats. Heliyon 6 37916105

Missed literature

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

No submissions yet.