Affinage

HMGCR

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

Length
888 aa
Mass
97.5 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HMGCR is the rate-limiting enzyme of the mevalonate pathway, catalyzing the conversion of HMG-CoA to mevalonate for cholesterol and isoprenoid biosynthesis, and its activity is subject to multilayered transcriptional, post-transcriptional, and post-translational regulation. Transcriptionally, HMGCR is controlled by SREBP-2 acting through dual sterol-regulatory elements in its promoter, with AMPK-mediated SREBP-2 phosphorylation suppressing expression (PMID:28342963, PMID:25933205); post-transcriptionally, HNRNPA1-dependent alternative splicing of exon 13 (modulated by SNP rs3846662) produces a catalytically inactive isoform (PMID:18802019, PMID:24001602), and multiple miRNAs (miR-21, miR-29, miR-195) target the HMGCR 3′UTR to reduce mRNA stability (PMID:25605429, PMID:28112179). Post-translationally, lanosterol-stimulated ubiquitylation by UBE2G2 and UBXD8-dependent ERAD drives proteasomal degradation, counterbalanced by mTORC1-phosphorylated USP20 deubiquitylase that stabilizes HMGCR in the fed state (PMID:31455613, PMID:28882874, PMID:30658189, PMID:33177714). Downstream, HMGCR-derived geranylgeranyl pyrophosphate is essential for prenylation of Rho/Rab GTPases governing vascular stability, innate immune inflammasome activation, and integrin signaling, and bi-allelic loss-of-function HMGCR variants cause autosomal-recessive limb-girdle muscular dystrophy rescuable by oral mevalonolactone (PMID:23206891, PMID:39012939, PMID:37167966, PMID:36745799).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2007 High

    Establishing HMGCR as a metabolic node downstream of insulin receptor signaling: tissue-specific RNAi in Drosophila corpus allatum showed that InR controls Hmgcr expression and that Hmgcr loss phenocopies InR loss for body size and sexual dimorphism of locomotion.

    Evidence GAL4/UAS-driven RNAi of InR and Hmgcr in Drosophila corpus allatum with phenotypic analysis

    PMID:17264888

    Open questions at the time
    • Whether this InR→Hmgcr axis operates in mammalian endocrine tissues
    • Mechanism of InR-mediated transcriptional control of Hmgcr
  2. 2008 High

    Defining how genetic variation controls HMGCR isoform balance: the intronic SNP rs3846662 modulates exon 13 splicing, and the exon-13-skipped isoform is catalytically dead, establishing that alternative splicing is a physiologically relevant mode of HMGCR regulation.

    Evidence Minigene splicing assay, enzymatic complementation in HMGCR-deficient UT-2 cells, human lymphoblastoid cell lines

    PMID:18802019

    Open questions at the time
    • Trans-acting factors mediating the splicing switch were unknown at this time
    • In vivo impact on plasma LDL-C was correlational
  3. 2010 Medium

    Characterizing the statin-binding flap domain: mutagenesis showed that the flap domain directly modulates substrate affinity and statin inhibition kinetics, revealing a structural basis for pharmacological targeting.

    Evidence Site-directed mutagenesis of purified recombinant HMGCR with steady-state enzyme kinetics

    PMID:21355415

    Open questions at the time
    • No crystal structure of mutant enzyme was solved
    • In vivo relevance of flap domain variants not tested
  4. 2012 High

    Linking HMGCR to non-cholesterol outputs in vascular biology: HMGCR inhibition in zebrafish caused cerebral hemorrhage rescued specifically by GGPP, and GGTase-I depletion phenocopied HMGCR loss, establishing protein geranylgeranylation (including Cdc42 prenylation) as the critical downstream branch for vascular stability.

    Evidence Pharmacological inhibition, morpholino knockdown, GGPP rescue in zebrafish with live imaging

    PMID:23206891

    Open questions at the time
    • Specific prenylated GTPase substrates beyond Cdc42 not individually tested
    • Translation to mammalian cerebrovascular biology not demonstrated
  5. 2013 High

    Identifying the trans-acting splicing factor for HMGCR exon 13: HNRNPA1 directly binds the rs3846662 region and promotes exon 13 skipping in an allele-dependent manner, reducing HMGCR activity and increasing LDL-C uptake.

    Evidence RNA-binding assay, HNRNPA1 overexpression, HMGCR enzyme activity and LDL uptake assays in hepatoma cells

    PMID:24001602

    Open questions at the time
    • Whether other splicing factors cooperate with HNRNPA1 at this site
    • In vivo validation in liver tissue not performed
  6. 2015 Medium

    Expanding transcriptional and post-transcriptional control: AMPK phosphorylates SREBP-2 to suppress HMGCR transcription, an estrogen response element in the HMGCR promoter mediates E2-dependent upregulation, and miR-21 and miR-195 directly target the HMGCR 3′UTR to reduce expression.

    Evidence AMPK kinase assay and TSH receptor KO mice; ERE identification with in vivo ovarian stimulation; luciferase 3′UTR reporter assays for miRNAs

    PMID:25605429 PMID:25933205 PMID:25961186 PMID:26632252

    Open questions at the time
    • Relative quantitative contribution of each miRNA in physiological contexts unknown
    • Estrogen-dependent regulation not validated in primary human hepatocytes
  7. 2017 High

    Resolving the ERAD machinery for sterol-induced HMGCR degradation: an unbiased haploid genetic screen identified UBXD8 as essential for extracting ubiquitylated HMGCR from the ER membrane for proteasomal degradation, and SREBP-2 was shown to activate HMGCR transcription via dual SREs requiring high SREBP-2 levels.

    Evidence Haploid CRISPR screen with endogenous HMGCR-mNeon tag; luciferase reporter, EMSA, and ChIP for SREBP-2/SRE characterization

    PMID:28342963 PMID:28882874

    Open questions at the time
    • How UBXD8 cooperates with p97/VCP for HMGCR extraction not fully delineated
    • Threshold model of SREBP-2 levels not tested across nutritional states in vivo
  8. 2018 High

    Identifying the dedicated E2 enzyme and a pathogenic autoantibody mechanism: UBE2G2 was identified as the specific E2 ubiquitin-conjugating enzyme for sterol-stimulated HMGCR ubiquitylation, and anti-HMGCR autoantibodies from immune-mediated necrotizing myopathy patients were shown to bind sarcolemmal HMGCR and activate the classical complement pathway.

    Evidence CRISPR E2 screen with ubiquitylation assays; immunostaining of primary muscle cells with patient autoantibodies and complement deposition quantification

    PMID:29330311 PMID:30658189

    Open questions at the time
    • E3 ligase partnering with UBE2G2 for HMGCR ubiquitylation not definitively identified in this study
    • Whether complement activation alone is sufficient for full IMNM pathology
  9. 2019 High

    Identifying the physiological sterol signal: lanosterol was established as the endogenous sterol intermediate that specifically triggers HMGCR degradation, while other C4-dimethylated intermediates regulate both HMGCR degradation and SREBP-2 cleavage.

    Evidence Systematic CRISPR deletion of mevalonate pathway enzymes combined with lipidomics in HeLa cells

    PMID:31455613

    Open questions at the time
    • Whether lanosterol acts by direct binding to the HMGCR sterol-sensing domain or via Insig was not resolved
    • In vivo validation of individual sterol contributions not performed
  10. 2020 High

    Discovering the fed-state stabilization mechanism: mTORC1 phosphorylates USP20 at S132/S134 in response to insulin/glucose, recruiting USP20 to deubiquitylate and stabilize HMGCR, directly coupling nutritional state to cholesterol biosynthetic flux.

    Evidence Liver-specific Usp20 KO, USP20 phosphosite knock-in mice, co-IP, ubiquitylation assays, rescue with HMGCR(K248R)

    PMID:33177714

    Open questions at the time
    • Whether USP20 also stabilizes other ER-resident mevalonate pathway enzymes
    • Quantitative contribution relative to transcriptional regulation in vivo
  11. 2022 High

    Extending HMGCR function to central metabolic control: Hmgcr in Drosophila insulin-producing neurons regulates insulin-like peptide expression, lipid storage, and feeding behavior via the α-glucosidase Tobi, and hypothalamic HMGCR inhibition in rodents stimulates food intake, establishing a conserved central role.

    Evidence Drosophila tissue-specific RNAi with genetic epistasis; rat/mouse intrahypothalamic drug injection

    PMID:35326421

    Open questions at the time
    • Mammalian downstream mediators of hypothalamic HMGCR signaling not identified
    • Whether the effect is prenylation-dependent or cholesterol-dependent in neurons
  12. 2022 High

    Confirming complement as the effector in anti-HMGCR myopathy: C5 complement inhibition with zilucoplan prevented anti-HMGCR antibody-mediated myofiber injury in a humanized mouse model, validating C5b-9 membrane attack complex as the mechanistic effector.

    Evidence Purified anti-HMGCR IgG with human complement in multiple mouse models; zilucoplan pharmacological rescue

    PMID:36009583

    Open questions at the time
    • Whether upstream complement components could also be targeted therapeutically
    • Long-term efficacy in human IMNM not tested
  13. 2023 High

    Establishing HMGCR as a Mendelian disease gene: bi-allelic loss-of-function missense variants cause autosomal-recessive limb-girdle muscular dystrophy, with decreased enzymatic activity and protein stability confirmed in vitro, and oral mevalonolactone rescues the disease phenotype in patients and statin myopathy in mice.

    Evidence WES across five families, enzymatic activity/stability assays, mevalonolactone oral administration rescue in human and mouse

    PMID:36745799 PMID:37167966

    Open questions at the time
    • Tissue-specific mevalonate pathway insufficiency (muscle vs. other tissues) not fully characterized
    • Long-term outcomes of mevalonolactone supplementation unknown
  14. 2024 High

    Connecting HMGCR to innate immune inflammasome activation: under metabolic stress, reduced HMGCR-derived GGPP impairs Rac1 prenylation, causing non-prenylated Rac1 to bind IQGAP1 and activate the NLRP3 inflammasome, validated in patient monocytes from mevalonate kinase deficiency.

    Evidence GGPP rescue, Rac1 prenylation assay, IQGAP1 co-IP, NLRP3 activation assay in human monocytes including patient cells

    PMID:39012939

    Open questions at the time
    • Whether other non-prenylated GTPases contribute to NLRP3 activation
    • Quantitative threshold of GGPP depletion required for inflammasome activation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the identity of the E3 ubiquitin ligase that partners with UBE2G2 for physiological sterol-induced HMGCR degradation, whether lanosterol directly engages the HMGCR sterol-sensing domain or acts via Insig, and the structural basis of HMGCR oligomerization changes caused by disease-associated variants.
  • E3 ligase identity for canonical sterol-induced degradation
  • Structural mechanism of lanosterol-sensing domain engagement
  • Full in vivo characterization of prenylation-dependent vs. cholesterol-dependent HMGCR functions across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016491 oxidoreductase activity 4
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1430728 Metabolism 10 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
BRCC36HNRNPA1HSP90AA1SIAH1SREBF2UBE2G2UBXD8USP20

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 USP20 deubiquitylase stabilizes HMGCR in the fed state: mTORC1 phosphorylates USP20 at S132 and S134 in response to postprandial insulin/glucose, which recruits USP20 to the HMGCR complex and antagonizes HMGCR ubiquitin-dependent degradation, thereby increasing cholesterol biosynthesis. Liver-specific Usp20 knockout mice, USP20(S132A/S134A) knock-in mice, co-immunoprecipitation, in vivo and in vitro ubiquitylation assays, rescue with constitutively stable HMGCR(K248R) Nature High 33177714
2019 Lanosterol is the bona fide endogenous sterol intermediate that specifically stimulates HMGCR degradation; other C4-dimethylated sterol intermediates (24,25-dihydrolanosterol, FFMAS, TMAS, dihydro-TMAS) regulate both HMGCR degradation and SREBP-2 cleavage inhibition, as demonstrated by CRISPR/Cas9 deletion of individual mevalonate pathway enzymes and lipidomics. CRISPR/Cas9 gene deletion of mevalonate pathway enzymes, lipidomics, immunoblot for HMGCR and SREBP-2 status in HeLa cells expressing mevalonate transporter Journal of lipid research High 31455613
2017 UBXD8 is an essential mediator of sterol-stimulated proteasomal degradation of HMGCR: it is required for dislocation of ubiquitylated HMGCR from the ER membrane en route to proteasomal degradation, a function dependent on its UBX domain. Haploid mammalian genetic screen with CRISPR/Cas9-tagged endogenous HMGCR-mNeon, UBXD8 ablation in multiple cell types, domain mutagenesis Arteriosclerosis, thrombosis, and vascular biology High 28882874
2018 UBE2G2 is the E2 ubiquitin-conjugating enzyme specifically required for sterol-stimulated ubiquitylation and degradation of HMGCR (distinct from SQLE which uses UBE2J2), identified by CRISPR/Cas9 screen of ERAD-associated E2 enzymes. CRISPR/Cas9-based E2 enzyme screen, ubiquitylation assays, HMGCR protein stability measurements in multiple human cell types Atherosclerosis High 30658189
2008 An intronic SNP (rs3846662) in HMGCR modulates alternative splicing of exon 13; the minor allele is associated with up to 2.2-fold lower expression of the exon-13-skipped isoform, and the alternative splice variant lacking exon 13 cannot restore HMGCR enzymatic activity in HMGCR-deficient UT-2 cells. Minigene transfection splicing assay, in vitro complementation assay in HMGCR-deficient UT-2 cells, human lymphoblastoid cell lines Arteriosclerosis, thrombosis, and vascular biology High 18802019
2013 HNRNPA1 directly binds the rs3846662 SNP site in HMGCR pre-mRNA and promotes exon 13 skipping in an allele-dependent manner; HNRNPA1 overexpression also specifically stabilizes the exon-13-skipped HMGCR transcript, reduces HMGCR enzyme activity, enhances LDL-C uptake, and increases cellular apoB. HNRNPA1 RNA-binding assay, HNRNPA1 overexpression, HMGCR enzyme activity assay, LDL uptake assay, hepatoma cell lines Human molecular genetics High 24001602
2024 BRCC36 deubiquitinates HMGCR in a DUB activity-dependent manner; HMGCR localization shifts from mitochondria during ferroptosis to the endoplasmic reticulum during pyroptosis, and BRCC36-mediated HMGCR stabilization inhibits ferroptosis while promoting pyroptosis. Co-immunoprecipitation, deubiquitylation assay, immunofluorescence subcellular localization, BRCC36 inhibitor (thiolutin), cell death assays Advanced science Medium 38178583
2023 SIAH1, an E3 ubiquitin ligase, ubiquitinates HMGCR, thereby modulating cholesterol synthesis and efflux protein activity in lung cancer cells; SIAH1 overexpression suppresses tumor growth and enhances cisplatin sensitivity in vivo. Co-immunoprecipitation, ubiquitylation assay, HMGCR knockdown and SIAH1 overexpression in vitro and xenograft models Cancer cell international Medium 37062828
2017 SREBP-2 activates human HMGCR transcription via two sterol-regulatory elements (SREs) and one NF-Y site in the HMGCR promoter; HMGCR expression is highly activated only when SREBP-2 levels are very high, unlike LDLR which responds at lower SREBP-2 levels. Luciferase reporter assays with SRE/NF-Y mutant library, electrophoretic mobility shift assay (EMSA), ChIP-PCR Biochimica et biophysica acta. Molecular and cell biology of lipids High 28342963
2015 An estrogen response element (ERE) in the HMGCR promoter mediates estradiol-dependent upregulation of HMGCR expression in hepatocytes, leading to increased cholesterol synthesis. Promoter ERE identification, E2 treatment of HepG2 cells and mouse fetal hepatocytes, in vivo ovarian stimulation mouse model with HMGCR expression measurement Scientific reports Medium 25961186
2012 HMGCR pathway activity in zebrafish is required for developmental cerebral vascular stability through protein geranylgeranylation: HMGCR inhibition causes cerebral hemorrhage rescued by geranylgeranyl pyrophosphate (GGPP) supplementation; depletion of GGTase-I (β-subunit) mimics HMGCR loss-of-function and reduces endothelial Cdc42 expression. Pharmacological HMGCR inhibition, genetic morpholino knockdown of GGTase-I β-subunit, GGPP rescue in zebrafish, live imaging Developmental biology High 23206891
2007 In Drosophila, Hmgcr expression in the corpus allatum (juvenile hormone-producing gland) is controlled by the insulin receptor (InR); RNAi-InR reduces both InR and Hmgcr expression, and RNAi-Hmgcr blocks HMGCR, both disrupting sexual dimorphism of locomotor activity and producing dwarf flies, placing HMGCR downstream of InR in a pathway controlling body size and JH synthesis. Tissue-specific RNAi in corpus allatum using GAL4/UAS system, phenotypic analysis of locomotion and body size PloS one High 17264888
2022 The statin target Hmgcr in insulin-producing cells of the Drosophila pars intercerebralis (hypothalamic equivalent) regulates energy metabolism and feeding behavior: inhibiting central Hmgcr reduces insulin-like peptide expression, impairs insulin signaling, increases lipid storage, causes hyperglycemia, and induces hyperphagia dependent on the insulin-regulated α-glucosidase Tobi. In rats and mice, acute hypothalamic Hmgcr inhibition stimulates food intake. Drosophila tissue-specific RNAi, pharmacological inhibition, genetic epistasis with tobi, rat/mouse intrahypothalamic drug injection Cells High 35326421
2024 Under glucose-oxygen deprivation in human monocytes, HMGCR function is constrained, reducing GGPP synthesis, which leads to decreased prenylation of Rac1, increased binding of non-prenylated Rac1 to IQGAP1, and NLRP3 inflammasome activation and IL-1β release. GGPP supplementation rescue, Rac1 prenylation assay, IQGAP1 co-immunoprecipitation, NLRP3 inflammasome activation assay, patient monocytes from mevalonate kinase deficiency and Muckle-Wells syndrome Science signaling High 39012939
2023 Bi-allelic loss-of-function missense variants in HMGCR cause autosomal-recessive limb-girdle muscular dystrophy; protein activity studies confirmed decreased enzymatic activity and reduced protein stability for variants p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln; molecular modeling showed variants are destabilizing and affect protein oligomerization. Whole exome sequencing, protein enzymatic activity assay, protein stability assay, molecular modeling, muscle biopsy histology American journal of human genetics High 37167966
2023 A pathogenic homozygous loss-of-function missense mutation in HMGCR causes human limb-girdle muscular disease; mevalonolactone (mevalonate pathway product downstream of HMGCR) administered orally to patients rescues the disease phenotype and also resolves statin-induced myopathy in mice, demonstrating that HMGCR loss-of-function myopathy is caused by mevalonate pathway insufficiency. Homozygosity mapping, WES, functional analysis by confocal microscopy and biochemical/biophysical methods, mevalonolactone synthesis and oral administration in mice and human patient Proceedings of the National Academy of Sciences of the United States of America High 36745799
2018 HSP90 physically interacts with HMGCR (by co-immunoprecipitation) and stabilizes HMGCR protein by inhibiting its degradation in hepatocellular carcinoma cells. Co-immunoprecipitation, HSP90 inhibition, HMGCR protein stability assay, cell growth and migration assays Molecular medicine reports Medium 30483734
2017 lncRNA ZFAS1 stabilizes HMGCR mRNA through U2AF2 (an RNA-binding protein): RNA pulldown and RIP assays demonstrate ZFAS1 binds U2AF2, which in turn binds HMGCR mRNA and increases its stability and expression in pancreatic carcinoma cells. RNA pulldown, RNA immunoprecipitation (RIP) assay, ZFAS1/U2AF2 knockdown, HMGCR mRNA stability assay Journal of immunology research Medium 35846429
2021 hnRNPR acts as a post-transcriptional repressor of HMGCR: it binds the 3'UTR of HMGCR mRNA (demonstrated by RNA immunoprecipitation and luciferase reporter assay) and reduces HMGCR mRNA stability and translation, thereby decreasing neuronal cholesterol levels. RNA immunoprecipitation, luciferase 3'UTR reporter assay, hnRNPR knockdown/overexpression in neuroblastoma cells, cholesterol measurement Journal of integrative neuroscience Medium 34258925
2010 Rational mutagenesis of the flap domain of human HMGCR (which has a role in statin binding) produces a catalytically active enzyme with ~38% decrease in K(app)M for substrate, ~2-fold increase in turnover number, and 480% increase in Ki for lovastatin, demonstrating that the flap domain is mechanistically important for statin inhibition. Site-directed mutagenesis, purified recombinant protein enzyme kinetics assay with wild-type and mutant HMGCR Indian journal of biochemistry & biophysics Medium 21355415
2020 HMGCR inhibition in renal cell carcinoma stabilizes the glycolytic enzyme PKM2 through increased HSP90 expression, promoting glycolysis and tumor growth; this effect is reversible by glycolysis inhibition with Shikonin (PKM2 inhibitor). HMGCR inhibition in RCC xenograft and cell models, HSP90/PKM2 protein level measurement, Seahorse glycolysis assay, pharmacological rescue PLoS biology Medium 33905408
2020 NPY stimulates hepatic cholesterol synthesis acutely via Y1 and Y5 receptors, activating the ERK1/2 signaling pathway to increase SREBP-2 processing and HMGCR protein expression, leading to cholesterol accumulation in hepatocytes. In vivo intraportal NPY injection in rats, BRL-3A hepatocyte culture with Y1/Y2/Y5 receptor antagonists and ERK1/2 antagonist, western blotting for HMGCR and SREBP-2 Life sciences Medium 32976883
2021 AMPK downregulates HMGCR in regulatory T cells, which activates p38 MAPK that phosphorylates GSK-3β, reducing PD-1 expression; deletion of AMPKα1 in Tregs promotes HMGCR expression and increases PD-1. AMPKα1-conditional knockout in Tregs (Foxp3YFP-Cre mice), flow cytometry, western blotting, immunoprecipitation, immunofluorescence, tumor growth assays Molecular cancer Medium 34649584
2020 In BRAF-inhibitor resistant melanomas with suppressed PGC1α, statin (HMGCR inhibitor) vulnerability is mechanistically linked to reduced RAB6B and RAB27A prenylation, which impairs their membrane association and disrupts integrin-FAK signaling required for growth; re-expression of RAB6B and RAB27A reverses statin vulnerability. Pharmacological screen, siRNA knockdown and overexpression of RAB6B/RAB27A, prenylation assay, integrin-FAK signaling assay, cell viability assays Nature communications Medium 37277330
2018 Anti-HMGCR autoantibodies from IMNM patients bind HMGCR protein present on the sarcolemma of myofibers and activate the classical complement pathway (IgG deposition and complement cascade activation), leading to myofiber necrosis; the degree of sarcolemmal complement deposits correlates with fiber necrosis (r=0.4, p=0.004). In vitro immunostaining of primary muscle cells with purified patient-derived autoantibodies, reverse transcription PCR, immunostaining of muscle biopsies, complement deposition quantification Neurology Medium 29330311
2022 C5 complement inhibition (zilucoplan) prevents anti-HMGCR antibody-mediated necrotizing myopathy in a humanized mouse model, demonstrating that C5b-9 complement membrane attack complex deposition downstream of anti-HMGCR IgG is mechanistically required for myofiber injury. Co-injection of purified anti-HMGCR IgG with human complement into C57BL/6, C5-deficient B10, and Rag2-/- mice; zilucoplan treatment; muscle strength measurement, C5b-9 immunostaining, fiber regeneration quantification Biomedicines High 36009583
2020 Discovery of an orally active VHL-recruiting PROTAC (21c) that induces proteasomal degradation of HMGCR (DC50=120 nmol/L in Insig-silenced HepG2 cells) by forming a ternary complex with VHL E3 ligase and HMGCR, demonstrating that HMGCR can be degraded through VHL-mediated ubiquitin-proteasome pathway. PROTAC synthesis, HMGCR protein degradation assay, DC50 measurement, molecular modeling of ternary complex, in vivo cholesterol reduction in hypercholesterolemic mice Acta pharmaceutica Sinica. B Medium 34094835
2008 CREM isoforms regulate the circadian expression of HMGCR in mouse liver: in Crem-/- livers, HMGCR circadian phase is advanced (from CT20 to CT12), coinciding with phase advance of the lathosterol/cholesterol ratio, but HMGCR proximal promoter is not directly responsive to CREMtau/ICER overexpression. Crem knockout mice, circadian expression profiling, GC-MS sterol analysis, promoter luciferase assay Biochemical and biophysical research communications Medium 18775413
2012 Maternal low-protein diet causes promoter hypomethylation and histone modification changes (decreased H3K9me1 and H3K27me3, increased H3 acetylation) at the HMGCR gene in offspring piglet livers, associated with increased HMGCR mRNA, protein expression, and enzyme activity. Bisulfite sequencing/MSP for DNA methylation, ChIP for histone modifications, HMGCR mRNA/protein measurement, enzymatic activity assay The Journal of nutritional biochemistry Medium 22444501
2015 HMGCR is a direct target of hsa-miR-195 in breast cancer cells; ectopic miR-195 expression reduces HMGCR protein levels, decreasing cellular cholesterol and triglyceride levels and inhibiting proliferation, invasion, and migration. Luciferase reporter assay (3'UTR targeting), miR-195 overexpression, cholesterol/triglyceride measurement, functional assays Scientific reports Medium 26632252
2015 HMGCR is a direct target of miR-21 in hepatocytes: luciferase reporter assay confirmed miR-21 targets the HMGCR 3'UTR, and miR-21 reduces HMGCR mRNA and protein levels, decreasing triglycerides and cholesterol in a NAFLD cell model; HMGCR overexpression attenuates this effect. Luciferase 3'UTR reporter assay, miR-21 transfection in HepG2 cells, HMGCR overexpression rescue, lipid measurement International journal of molecular medicine Medium 25605429
2017 miR-29a/b/c suppress HMGCR expression by directly targeting HMGCR mRNA 3'UTR (validated by luciferase reporter), and miR-29a overexpression in hepatic cells reduces HMGCR protein and free cholesterol levels; Dicer1/miR-29 axis regulates hepatic free cholesterol accumulation. miRNA screening, luciferase 3'UTR reporter assay, miR-29a overexpression, HMGCR protein measurement, liver-specific Dicer1 knockout mice Acta pharmacologica Sinica Medium 28112179
2015 AMPK activation (by AICAR) directly inhibits SREBP-2 and its target gene HMGCR: AMPK phosphorylates threonine residues in both precursor and nuclear SREBP-2 forms, suppressing HMGCR expression and antagonizing TSH-stimulated HMGCR upregulation in hepatocytes. AICAR treatment of HepG2 cells and TSH receptor KO mice, AMPK kinase assay, SREBP-2 phosphorylation assay, HMGCR mRNA/protein measurement PloS one Medium 25933205
2024 HMGCR promotes stemness and metastasis of hepatocellular carcinoma via activation of Hedgehog signaling: HMGCR positively correlates with Smoothened receptor expression and facilitates nuclear translocation of GLI1; Hedgehog pathway inhibition reverses HMGCR-driven stemness and metastasis. HMGCR overexpression/knockdown, Hedgehog pathway inhibitor screen, GLI1 nuclear translocation assay, in vitro stemness/metastasis assays and in vivo tumor models Genes & diseases Medium 39022130

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study. Journal of the American College of Cardiology 326 25770315
2013 Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). The Journal of biological chemistry 296 23696639
2020 Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis. Nature 209 33177714
2015 MicroRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1. Scientific reports 157 26632252
2018 Necrosis in anti-SRP+ and anti-HMGCR+myopathies: Role of autoantibodies and complement. Neurology 147 29330311
2015 miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR. International journal of molecular medicine 118 25605429
2013 Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle & nerve 110 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 96 25866831
2015 Myopathy with anti-HMGCR antibodies: Perimysium and myofiber pathology. Neurology(R) neuroimmunology & neuroinflammation 84 26090508
2019 Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing. Journal of lipid research 82 31455613
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 78 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 73 28342963
2016 Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy. Neurology(R) neuroimmunology & neuroinflammation 72 27761483
2020 Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo. Acta pharmaceutica Sinica. B 67 34094835
2015 AICAR-Induced Activation of AMPK Inhibits TSH/SREBP-2/HMGCR Pathway in Liver. PloS one 62 25933205
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 61 34681767
2010 Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin. Arteriosclerosis, thrombosis, and vascular biology 59 20413733
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
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
2015 HMGCR positively regulated the growth and migration of glioblastoma cells. Gene 49 26432005
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 45 31953433
2012 Maternal low-protein diet causes epigenetic deregulation of HMGCR and CYP7α1 in the liver of weaning piglets. The Journal of nutritional biochemistry 45 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 43 36745799
2017 Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis. Acta pharmacologica Sinica 41 28112179
2023 Anti-HMGCR immune-mediated necrotising myopathy: Addressing the remaining issues. Autoimmunity reviews 39 37884200
2018 Long noncoding RNA lncARSR promotes hepatic cholesterol biosynthesis via modulating Akt/SREBP-2/HMGCR pathway. Life sciences 38 29678744
2024 BRCC36 Deubiquitinates HMGCR to Regulate the Interplay Between Ferroptosis and Pyroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 37 38178583
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
2015 High Maternal Serum Estradiol Levels Induce Dyslipidemia in Human Newborns via a Hepatic HMGCR Estrogen Response Element. Scientific reports 35 25961186
2018 Hexane-Isopropanolic Extract of Tungrymbai, a North-East Indian fermented soybean food prevents hepatic steatosis via regulating AMPK-mediated SREBP/FAS/ACC/HMGCR and PPARα/CPT1A/UCP2 pathways. Scientific reports 33 29968750
2018 Differential use of E2 ubiquitin conjugating enzymes for regulated degradation of the rate-limiting enzymes HMGCR and SQLE in cholesterol biosynthesis. Atherosclerosis 32 30658189
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 30 31270304
2014 The inhibitory effects of bioactive compounds of tomato juice binding to hepatic HMGCR: in vivo study and molecular modelling. PloS one 30 24392102
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
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
2023 Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy. American journal of human genetics 27 37167966
2022 Pretreatment of hydroethanolic extract of Dillenia indica L. attenuates oleic acid induced NAFLD in HepG2 cells via modulating SIRT-1/p-LKB-1/AMPK, HMGCR & PPAR-α signaling pathways. Journal of ethnopharmacology 27 35351574
2016 Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia. Pharmacogenetics and genomics 26 26466344
2024 Inhibiting HMGCR represses stemness and metastasis of hepatocellular carcinoma via Hedgehog signaling. Genes & diseases 24 39022130
2022 The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway. Journal of pharmaceutical analysis 24 36820075
2019 Anti-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibody in necrotizing myopathy: treatment outcomes, cancer risk, and role of autoantibody level. Scandinavian journal of rheumatology 23 31801390
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
2011 Effect of HMGCR variant alleles on low-density lipoprotein cholesterol-lowering response to atorvastatin in healthy Korean subjects. Journal of clinical pharmacology 23 21427285
2022 Prevention of Anti-HMGCR Immune-Mediated Necrotising Myopathy by C5 Complement Inhibition in a Humanised Mouse Model. Biomedicines 22 36009583
2021 HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma. PLoS biology 22 33905408
2019 YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine. Biomolecules 22 31627466
2020 NPY stimulates cholesterol synthesis acutely by activating the SREBP2-HMGCR pathway through the Y1 and Y5 receptors in murine hepatocytes. Life sciences 20 32976883
2022 Perivascular and endomysial macrophages expressing VEGF and CXCL12 promote angiogenesis in anti-HMGCR immune-mediated necrotizing myopathy. Rheumatology (Oxford, England) 19 34864921
2022 Rewiring Lipid Metabolism by Targeting PCSK9 and HMGCR to Treat Liver Cancer. Cancers 19 36612001
2010 The relationship between HMGCR genetic variation, alternative splicing, and statin efficacy. Discovery medicine 19 20587337
2023 Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas. Nature communications 18 37277330
2022 CAPRIN2 upregulation by LINC00941 promotes nasopharyngeal carcinoma ferroptosis resistance and metastatic colonization through HMGCR. Frontiers in oncology 17 36276162
2021 Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction. Acta pharmacologica Sinica 17 34588618
2016 Effect of tomato juice consumption on the plasmatic lipid profile, hepatic HMGCR activity, and fecal short chain fatty acid content of rats. Food & function 17 27711850
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 16 38103317
2022 lncRNA ZFAS1 Promotes HMGCR mRNA Stabilization via Binding U2AF2 to Modulate Pancreatic Carcinoma Lipometabolism. Journal of immunology research 16 35846429
2021 Polyphenols from Citrus Tacle® Extract Endowed with HMGCR Inhibitory Activity: An Antihypercholesterolemia Natural Remedy. Molecules (Basel, Switzerland) 16 34577189
2020 Anti-HMGCR Antibody-Positive Myopathy Shows Bcl-2-Positive Inflammation and Lymphocytic Accumulations. Journal of neuropathology and experimental neurology 14 32100014
2020 BAI1 acts as a tumor suppressor in lung cancer A549 cells by inducing metabolic reprogramming via the SCD1/HMGCR module. Carcinogenesis 14 32255478
2019 Statin-induced anti-HMGCR antibody-related immune-mediated necrotising myositis achieving complete remission with rituximab. BMJ case reports 14 31791994
2018 HSP90 interacts with HMGCR and promotes the progression of hepatocellular carcinoma. Molecular medicine reports 14 30483734
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
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 13 34830081
2017 Water-Soluble Polysaccharide Extracts from the Oyster Culinary-Medicinal Mushroom Pleurotus ostreatus (Agaricomycetes) with HMGCR Inhibitory Activity. International journal of medicinal mushrooms 13 29256842
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
2013 The effects of age and gender on the relationship between HMGCR promoter-911 SNP (rs33761740) and serum lipids in patients with coronary heart disease. Gene 13 23933271
2010 Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity. Indian journal of biochemistry & biophysics 13 21355415
2023 SIAH1 ubiquitination-modified HMGCR inhibits lung cancer progression and promotes drug sensitivity through cholesterol synthesis. Cancer cell international 12 37062828
2020 Statin Intolerance, Anti-HMGCR Antibodies, and Immune Checkpoint Inhibitor-Associated Myositis: A "Two-Hit" Autoimmune Toxicity or Clinical Predisposition? The oncologist 12 32400023
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
2022 High-Risk Polymorphisms Associated with the Molecular Function of Human HMGCR Gene Infer the Inhibition of Cholesterol Biosynthesis. BioMed research international 11 35707384
2020 Statin-associated anti-HMGCR immune-mediated necrotizing myopathy with dermatomyositis-like features: A case report. SAGE open medical case reports 11 33447390
2019 Anticancer auranofin engages 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as a target. Metallomics : integrated biometal science 11 31631207
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
2022 Identification of HMGCR, PPGARG and prohibitin as potential druggable targets of dihydrotestosterone for treatment against traumatic brain injury using system pharmacology. International immunopharmacology 10 35344815
2019 [Dermatomyositis-like syndrome revealing statin-induced necrotizing autoimmune myopathy with anti-HMGCR antibodies]. Annales de dermatologie et de venereologie 10 30929872
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
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
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 cDNA cloning, prokaryotic expression and functional analysis of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in Pogostemon cablin. Protein expression and purification 8 31301429
2018 Coexistence of anti-HMGCR and anti-MDA5 identified by an unlabeled immunoprecipitation assay in a chinese patient cohort with myositis. Medicine 8 30461626
2009 Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome. Fertility and sterility 8 19327767
2009 A HMGCR polymorphism is associated with relations between blood pressure and urinary sodium and potassium ratio in the Epic-Norfolk Study. Journal of the American Society of Hypertension : JASH 8 20409966