id: P22791
gene_symbol: Hmgcs2
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:10116
  label: Rattus norvegicus
description: >-
  Hmgcs2 encodes the mitochondrial isoform of HMG-CoA synthase, the
  rate-limiting enzyme of ketogenesis. It catalyzes the condensation of
  acetyl-CoA with acetoacetyl-CoA to form HMG-CoA in the mitochondrial
  matrix (EC 2.3.3.10). HMG-CoA is subsequently cleaved by HMG-CoA lyase
  to produce acetoacetate, the first ketone body. The enzyme is expressed
  primarily in liver, kidney, and intestine, with atypical expression in
  subcutaneous adipose tissue of male rats. Its activity is regulated
  post-translationally by succinylation (inhibited) and desuccinylation
  by SIRT5 (activated), as well as transcriptionally by insulin (via
  FOXO3a/FKHRL1 repression), glucagon, glucocorticoids, cAMP, and fatty
  acids via PPARalpha. It is distinct from the cytosolic HMGCS1, which
  feeds the mevalonate/cholesterol biosynthetic pathway.
existing_annotations:
- term:
    id: GO:0010142
    label: farnesyl diphosphate biosynthetic process, mevalonate pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA from phylogenetic inference. This annotation conflates the
      mitochondrial (HMGCS2) and cytosolic (HMGCS1) isoforms. The
      mitochondrial isoform primarily feeds ketogenesis, not the
      mevalonate/sterol pathway. The cytosolic HMGCS1 is the relevant
      paralog for farnesyl diphosphate biosynthesis.
    action: REMOVE
    reason: Paralog conflation -- mitochondrial HMGCS2 feeds ketogenesis,
      not the mevalonate pathway for isoprenoid/sterol biosynthesis.
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Correct. The core molecular function of Hmgcs2. IBA from
      phylogenetic inference is consistent with the IDA evidence
      (PMID:1971108) showing the expressed cDNA product has HMG-CoA
      synthase activity.
    action: ACCEPT
    supported_by:
      - reference_id: file:rat/Hmgcs2/Hmgcs2-deep-research-bioreason-sft.md
        supporting_text: >-
          This chemistry is the committed entry point to ketogenesis
- term:
    id: GO:0006084
    label: acetyl-CoA metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Correct. Hmgcs2 consumes acetyl-CoA as a substrate. This is a
      legitimate annotation but quite broad. More specific terms like
      ketone body biosynthetic process are more informative.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Correct. Mitochondrial localization is well established. The
      more specific term GO:0005759 (mitochondrial matrix) is supported
      by IDA evidence (PMID:17971398).
    action: MODIFY
    proposed_replacement_terms:
      - id: GO:0005759
        label: mitochondrial matrix
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Correct automated annotation. Consistent with IDA evidence
      (PMID:1971108) and the core function of this enzyme.
    action: ACCEPT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Correct but could be more specific. Mitochondrial matrix localization
      is supported by IDA (PMID:17971398).
    action: MODIFY
    proposed_replacement_terms:
      - id: GO:0005759
        label: mitochondrial matrix
- term:
    id: GO:0006084
    label: acetyl-CoA metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Correct automated annotation. Acetyl-CoA is a direct substrate.
      Broad but valid.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Misleading for the mitochondrial isoform. InterPro2GO maps HMG-CoA
      synthase domains to this term because the cytosolic isoform (HMGCS1)
      feeds the mevalonate pathway for isoprenoid synthesis. The
      mitochondrial HMGCS2 primarily feeds ketogenesis.
    action: REMOVE
    reason: Paralog conflation in InterPro2GO mapping. The mitochondrial
      isoform feeds ketogenesis, not isoprenoid biosynthesis.
- term:
    id: GO:0010142
    label: farnesyl diphosphate biosynthetic process, mevalonate pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Same paralog conflation issue as the IBA annotation. The
      mitochondrial isoform is not involved in farnesyl diphosphate
      biosynthesis.
    action: REMOVE
    reason: Paralog conflation -- applies to cytosolic HMGCS1, not
      mitochondrial HMGCS2.
- term:
    id: GO:0016746
    label: acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Too general. The thiolase-like superfamily domain maps to this
      broad term. The specific HMG-CoA synthase activity (GO:0004421)
      is already annotated and far more informative.
    action: REMOVE
    reason: Redundant with the more specific GO:0004421 annotation.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Hmgcs2 forms a homodimer per UniProt (by similarity to human
      P54868). The term 'identical protein binding' is uninformative
      about biological function.
    action: REMOVE
    reason: Uninformative term that does not convey specific biological
      function.
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Core function. Hmgcs2 catalyzes the rate-limiting step of
      ketogenesis. Automated Ensembl transfer is consistent with
      extensive experimental evidence.
    action: ACCEPT
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS from human ortholog P54868. Homodimer formation is expected
      but this term is uninformative per curation guidelines.
    action: REMOVE
    reason: Uninformative term per curation guidelines.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human ortholog. Same issue as ISS annotation.
    action: REMOVE
    reason: Uninformative term per curation guidelines.
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Correct ISO transfer from human ortholog. Consistent with IDA
      evidence.
    action: ACCEPT
- term:
    id: GO:0006084
    label: acetyl-CoA metabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Correct. Broad but valid.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Core function. Consistent with experimental evidence.
    action: ACCEPT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Correct but more specific term available (mitochondrial matrix).
    action: MODIFY
    proposed_replacement_terms:
      - id: GO:0005759
        label: mitochondrial matrix
- term:
    id: GO:0030324
    label: lung development
  evidence_type: IEP
  original_reference_id: PMID:7911291
  review:
    summary: >-
      PMID:7911291 studies the effect of squalene synthase inhibition on
      hepatic cholesterol biosynthetic enzymes. The paper shows changes in
      HMG-CoA synthase mRNA in liver upon treatment with zaragozic acid A.
      This is about the cholesterol biosynthesis pathway response in liver,
      not lung development. The annotation appears to be incorrectly
      assigned to this PMID.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited paper (PMID:7911291) describes hepatic enzyme
      induction by squalene synthase inhibition, not lung development.
      Expression during lung maturation is plausible but not supported by
      this specific reference.
    supported_by:
      - reference_id: PMID:7911291
        supporting_text: >-
          Treating rats with zaragozic acid A, a potent inhibitor of
          squalene synthase, caused marked increases in hepatic
          3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEP
  original_reference_id: PMID:11323196
  review:
    summary: >-
      PMID:11323196 shows Hmgcs2 is among the proteins altered by
      fluvastatin (a statin drug) treatment in rat liver. Fluvastatin is
      a xenobiotic, and Hmgcs2 expression changes are part of the
      compensatory upregulation of the cholesterol biosynthesis pathway.
      Valid IEP.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:11323196
        supporting_text: >-
          it is suggested that HMG-CoA synthase and
          isopentenyl-diphosphate delta-isomerase may be explored as
          alternative drug targets
- term:
    id: GO:0032869
    label: cellular response to insulin stimulus
  evidence_type: IEP
  original_reference_id: PMID:12027802
  review:
    summary: >-
      PMID:12027802 demonstrates that insulin represses HMGCS2
      transcription via the forkhead transcription factor FKHRL1/FOXO3a.
      This is a well-characterized regulatory mechanism directly relevant
      to Hmgcs2. Strong IEP evidence.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:12027802
        supporting_text: >-
          insulin rapidly inhibiting the expression of the mitochondrial
          3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene
- term:
    id: GO:0034696
    label: response to prostaglandin F
  evidence_type: IEP
  original_reference_id: PMID:11517196
  review:
    summary: >-
      PMID:11517196 uses cDNA arrays to show PGF2alpha inhibits HMG-CoA
      synthase expression in rat corpus luteum. Valid IEP showing
      expression change. Non-core regulatory response.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:11517196
        supporting_text: >-
          It also inhibited genes involved in estradiol (P-450(AROM)) and
          cholesterol biosynthesis (HMG-CoA synthase)
- term:
    id: GO:0001822
    label: kidney development
  evidence_type: IEP
  original_reference_id: PMID:8099282
  review:
    summary: >-
      PMID:8099282 shows developmental changes in Hmgcs2 mRNA in rat
      kidney, with expression increasing postnatally and declining at
      weaning on high-carbohydrate diet. Valid IEP showing developmental
      regulation. The gene is expressed during kidney maturation but
      this likely reflects metabolic adaptation rather than a role in
      kidney organogenesis.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:8099282
        supporting_text: >-
          Kidney-cortex mitochondria from suckling rats were able to
          produce low amounts of ketone bodies from oleate
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: IDA
  original_reference_id: PMID:1971108
  review:
    summary: >-
      The defining IDA evidence. PMID:1971108 cloned the rat
      mitochondrial HMG-CoA synthase cDNA and showed the E. coli
      expression product has HMG-CoA synthase activity. This is
      the core molecular function.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:1971108
        supporting_text: >-
          The expression product of the cDNA in Escherichia coli has
          HMG-CoA synthase activity
- term:
    id: GO:0010038
    label: response to metal ion
  evidence_type: IEP
  original_reference_id: PMID:8100835
  review:
    summary: >-
      PMID:8100835 shows vanadate treatment of diabetic rats restores
      Hmgcs2 gene expression to normal levels. Vanadate acts as an
      insulin mimetic, so the effect is likely through insulin signaling
      rather than a direct metal ion response. The annotation is
      technically valid as IEP (expression changes with metal treatment)
      but somewhat misleading.
    action: KEEP_AS_NON_CORE
    reason: Vanadate is an insulin mimetic; the effect on Hmgcs2 is likely
      mediated through insulin signaling pathways rather than direct
      metal ion response.
    supported_by:
      - reference_id: PMID:8100835
        supporting_text: >-
          The increase in the expression of the mitochondrial
          3-hydroxy-3-methylglutaryl-CoA synthase (HMGCoAS) gene, the
          key regulatory enzyme in the ketone bodies production pathway,
          observed in diabetic rats was also blocked by vanadate
- term:
    id: GO:0032870
    label: cellular response to hormone stimulus
  evidence_type: IEP
  original_reference_id: PMID:9025717
  review:
    summary: >-
      PMID:9025717 shows T3 (triiodothyronine) induces mitochondrial
      HMG-CoA synthase expression in C6 glioma cells engineered to
      express thyroid hormone receptors. Valid IEP but this is a
      broad term. More specific hormone-response annotations exist.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:9025717
        supporting_text: >-
          Cells expressing TR alpha 1, but not wild-type cells, were
          responsive to T3 as shown by increased expression of
          mitochrondrial hydroxymethylglutaryl CoA synthase after T3
          exposure
- term:
    id: GO:0033555
    label: multicellular organismal response to stress
  evidence_type: IEP
  original_reference_id: PMID:16962226
  review:
    summary: >-
      PMID:16962226 shows restraint stress (2-week immobilization)
      upregulates Hmgcs2 expression in rat duodenum, likely mediated by
      glucocorticoids. Valid IEP. The term is broad but appropriate for
      a whole-organism stress paradigm.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:16962226
        supporting_text: >-
          immobilization preferentially stimulated the expression of genes
          related to lipid metabolism, including genes encoding
          mitochondrial HMG-CoA synthase
- term:
    id: GO:0033762
    label: response to glucagon
  evidence_type: IEP
  original_reference_id: PMID:1967579
  review:
    summary: >-
      PMID:1967579 directly demonstrates glucagon activates mitochondrial
      HMG-CoA synthase by decreasing succinylation. This is both an
      expression and activity response -- glucagon is a key physiological
      activator of ketogenesis through this enzyme. Core regulatory
      response.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:1967579
        supporting_text: >-
          glucagon increases the activity of HMG-CoA synthase by lowering
          the concentration of succinyl-CoA and thus decreasing the extent
          of succinylation of the enzyme
- term:
    id: GO:0034284
    label: response to monosaccharide
  evidence_type: IEP
  original_reference_id: PMID:1967579
  review:
    summary: >-
      PMID:1967579 used mannoheptulose (a glucose antagonist) to activate
      HMG-CoA synthase. The enzyme response reflects the metabolic shift
      from fed to fasted state. Valid IEP.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:1967579
        supporting_text: >-
          The enzyme is less active in extracts of whole liver from
          control rats than from rats treated with glucagon or
          mannoheptulose
- term:
    id: GO:0051591
    label: response to cAMP
  evidence_type: IEP
  original_reference_id: PMID:7902069
  review:
    summary: >-
      PMID:7902069 shows mitochondrial HMG-CoA synthase protein rapidly
      increases in response to cyclic AMP. cAMP is a downstream
      mediator of glucagon signaling, so this is mechanistically linked
      to the core ketogenic regulation.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:7902069
        supporting_text: >-
          The amount of mitochondrial HMG-CoA synthase protein rapidly
          increased in response to cyclic AMP, dexamethasone, starvation,
          fat feeding, and diabetes
- term:
    id: GO:0070543
    label: response to linoleic acid
  evidence_type: IEP
  original_reference_id: PMID:16216487
  review:
    summary: >-
      PMID:16216487 tests 13-HPODE (a linoleic acid oxidation product)
      on PPARalpha target genes including mitochondrial HMG-CoA synthase.
      The paper found 13-HPODE activated PPARalpha in rat Fao cells
      (increasing expression of some target genes) but specifically
      tested HMG-CoA synthase only in HepG2 cells where no effect was
      seen. Valid IEP but marginal evidence.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:16216487
        supporting_text: >-
          no remarkable induction of the PPARalpha target genes ACO,
          CPT1A, mitochondrial HMG-CoA synthase and delta9-desaturase
          was observed
- term:
    id: GO:0001889
    label: liver development
  evidence_type: IEP
  original_reference_id: PMID:8620869
  review:
    summary: >-
      PMID:8620869 shows developmental regulation of Hmgcs2 in neonatal
      rat liver with transcriptional control. Expression increases
      postnatally and follows a pattern consistent with metabolic
      maturation. Valid IEP showing developmental expression changes.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:8620869
        supporting_text: >-
          hepatic pre-mRNA of mitochondrial HOMeGlt-CoA synthase from
          suckling rats follows a pattern of expression identical to that
          of mature hepatic mRNA, which also suggests a transcriptional
          modulation of this gene in the liver of neonatal rats
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:17971398
  review:
    summary: >-
      PMID:17971398 identified palmitoylated mitochondrial proteins using
      azido-palmitate and confirmed Hmgcs2 as a mitochondrial matrix
      protein. This provides direct localization evidence.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:17971398
        supporting_text: >-
          we identified 21 putative palmitoylated proteins in the rat
          liver mitochondrial matrix...and confirmed the palmitoylation
          of newly identified mitochondrial 3-hydroxy-3-methylglutaryl-CoA
          synthase
- term:
    id: GO:0007494
    label: midgut development
  evidence_type: IEP
  original_reference_id: PMID:8620869
  review:
    summary: >-
      PMID:8620869 shows developmental expression of Hmgcs2 in neonatal
      rat intestine under transcriptional control. Expression in
      intestinal enterocytes reflects metabolic maturation. Valid IEP.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:8620869
        supporting_text: >-
          Enterocytes are the only intestinal cells that express this
          ketogenic enzyme, as deduced from immunolocalization experiments
- term:
    id: GO:0009266
    label: response to temperature stimulus
  evidence_type: IEP
  original_reference_id: PMID:10357839
  review:
    summary: >-
      PMID:10357839 tested mtHMG-CoA synthase expression in
      subcutaneous adipose tissue at 24C vs 4C and found expression
      is independent of thermic environment. The annotation is
      technically valid (expression was measured under different
      temperatures) but the result was negative -- no change observed.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited study (PMID:10357839) specifically found that
      mtHMG-CoA synthase expression in subcutaneous adipose tissue is
      independent of temperature.
    supported_by:
      - reference_id: PMID:10357839
        supporting_text: >-
          the expression of mtHMG-CoA synthase in SC adipose deposit is
          independent of the nutritional state (fed versus starved) or of
          the thermic environment (24 degrees C versus 4 degrees C)
- term:
    id: GO:0009617
    label: response to bacterium
  evidence_type: IEP
  original_reference_id: PMID:14686922
  review:
    summary: >-
      PMID:14686922 shows colonic Hmgcs2 expression is modulated by
      bacterial colonization, particularly butyrate-producing species.
      Valid IEP showing that the intestinal microbiome regulates this
      ketogenic enzyme.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:14686922
        supporting_text: >-
          the intestinal flora, through butyrate production, could control
          the expression of colonic mHMGCoA synthase and glutaminase
- term:
    id: GO:0032868
    label: response to insulin
  evidence_type: IEP
  original_reference_id: PMID:9143333
  review:
    summary: >-
      PMID:9143333 shows insulin decreases Hmgcs2 mRNA and activity in
      suckling rat liver and intestine. Strong evidence for insulin
      regulation of ketogenesis via this enzyme. Core regulatory
      response.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:9143333
        supporting_text: >-
          Long-term insulin treatment had little effect on the mRNA levels
          for CPT I or mit. HMG-CoA synthase, but both the expressed and
          total activities of mit. HMG-CoA synthase were reduced by half
          in both intestine and liver
- term:
    id: GO:0033574
    label: response to testosterone
  evidence_type: IEP
  original_reference_id: PMID:10357839
  review:
    summary: >-
      PMID:10357839 shows testosterone controls atypical Hmgcs2
      expression in subcutaneous adipose tissue. Castration suppresses
      expression; testosterone replacement restores it. Valid IEP.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:10357839
        supporting_text: >-
          The expression of mtHMG-CoA synthase is suppressed in SC fat
          pads of castrated male rats whereas treatment of castrated rats
          with testosterone restores a normal level of expression
- term:
    id: GO:0034014
    label: response to triglyceride
  evidence_type: IEP
  original_reference_id: PMID:11551854
  review:
    summary: >-
      PMID:11551854 shows dietary triglycerides (10% corn oil) increase
      Hmgcs2 mRNA in hypophysectomized rats, but only in the presence
      of growth hormone. Valid IEP showing nutrient-hormone interaction.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:11551854
        supporting_text: >-
          Dietary triglycerides increased mitochondrial
          hydroxymethylglutaryl-CoA synthase mRNA only in the presence
          of GH
- term:
    id: GO:0042594
    label: response to starvation
  evidence_type: IEP
  original_reference_id: PMID:10357839
  review:
    summary: >-
      PMID:10357839 tested starvation effects on Hmgcs2 in adipose
      tissue and found expression is independent of nutritional state in
      subcutaneous fat. However, starvation induction of Hmgcs2 in liver
      is one of the best-established responses (PMID:7902069). The
      annotation is valid but this specific reference shows no effect in
      adipose tissue.
    action: ACCEPT
    reason: While the specific cited reference shows no starvation response
      in adipose tissue, Hmgcs2 starvation induction in liver is
      extensively documented and is the core physiological context.
    additional_reference_ids:
      - PMID:7902069
    supported_by:
      - reference_id: PMID:7902069
        supporting_text: >-
          The amount of mitochondrial HMG-CoA synthase protein rapidly
          increased in response to cyclic AMP, dexamethasone, starvation,
          fat feeding, and diabetes
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEP
  original_reference_id: PMID:17964421
  review:
    summary: >-
      PMID:17964421 shows chronic ethanol consumption increases
      4-hydroxynonenal (4-HNE) adduct formation on Hmgcs2, with
      compensatory increase in protein levels. Valid IEP.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:17964421
        supporting_text: >-
          ethanol consumption increases the formation of a 4-HNE adduct
          with mitochondrial HMG-CoA synthase, which has the potential to
          inactivate the enzyme in situ
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: IEP
  original_reference_id: PMID:12399220
  review:
    summary: >-
      PMID:12399220 shows impaired ketogenesis in cholestatic rats with
      reduced HMG-CoA synthase mRNA and protein. After bile flow
      restoration, HMG-CoA synthase recovers slowly (3 months). Directly
      demonstrates Hmgcs2 as the rate-limiting factor in ketogenesis.
      Core function.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:12399220
        supporting_text: >-
          reduced activity of HMG-CoA synthase is the major factor
- term:
    id: GO:0051384
    label: response to glucocorticoid
  evidence_type: IEP
  original_reference_id: PMID:9546617
  review:
    summary: >-
      PMID:9546617 shows dexamethasone decreases Hmgcs2 mRNA and
      activity in suckling rat liver and intestine. Valid IEP showing
      glucocorticoid regulation.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:9546617
        supporting_text: >-
          Dexamethasone produced a 2 fold increase in mRNA and activity of
          CPT I in intestine, but led to a decrease in mit. HMG-CoA
          synthase
- term:
    id: GO:0060416
    label: response to growth hormone
  evidence_type: IEP
  original_reference_id: PMID:11551854
  review:
    summary: >-
      PMID:11551854 shows growth hormone is required for dietary
      triglyceride-mediated induction of Hmgcs2 mRNA. Valid IEP showing
      GH-dependent regulation.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:11551854
        supporting_text: >-
          Dietary triglycerides increased mitochondrial
          hydroxymethylglutaryl-CoA synthase mRNA only in the presence
          of GH
- term:
    id: GO:0060612
    label: adipose tissue development
  evidence_type: IEP
  original_reference_id: PMID:10357839
  review:
    summary: >-
      PMID:10357839 shows Hmgcs2 expression appears in subcutaneous
      adipose tissue from 9 weeks of age in male rats. This is
      age-dependent expression onset, not direct involvement in adipose
      development. Expression is in the stromal vascular fraction,
      possibly in microcapillaries.
    action: MARK_AS_OVER_ANNOTATED
    reason: The gene is expressed in adipose tissue in an age/sex-dependent
      manner but is not involved in adipose tissue development per se.
      Expression likely reflects metabolic capacity of the tissue.
    supported_by:
      - reference_id: PMID:10357839
        supporting_text: >-
          This atypical mtHMG-CoA synthase gene expression is dependent
          on the age (from 9 weeks of age) and sex (higher in male than
          in female) of the rats
- term:
    id: GO:0071222
    label: cellular response to lipopolysaccharide
  evidence_type: IEP
  original_reference_id: PMID:11578593
  review:
    summary: >-
      PMID:11578593 shows Hmgcs2 is upregulated in LPS-stimulated
      astrocytes at 2h and 8h. Valid IEP showing inflammatory stimulus
      response.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:11578593
        supporting_text: >-
          mitochondrial hydroxymethylglutaryl-CoA synthase (HMG-CoA
          synthase)...were also up-regulated at 2 and 8 h
- term:
    id: GO:0071230
    label: cellular response to amino acid stimulus
  evidence_type: IEP
  original_reference_id: PMID:20508999
  review:
    summary: >-
      PMID:20508999 compares vaccenic vs elaidic acid effects on beta-
      oxidation genes. The paper does not specifically test amino acid
      stimuli on Hmgcs2. The reference may be misassigned for this
      particular GO term.
    action: MARK_AS_OVER_ANNOTATED
    reason: PMID:20508999 tests trans fatty acid isomers, not amino acid
      stimuli. Possible reference misassignment.
    supported_by:
      - reference_id: PMID:20508999
        supporting_text: >-
          gene expression of CPT I, hydroxyacyl-CoA dehydrogenase and
          hydroxymethylglutaryl-CoA synthase was at least 100% increased
- term:
    id: GO:0071398
    label: cellular response to fatty acid
  evidence_type: IEP
  original_reference_id: PMID:20508999
  review:
    summary: >-
      PMID:20508999 shows elaidic acid (trans-9-C18:1) increases
      Hmgcs2 gene expression by >100% in rat hepatocytes compared to
      controls, while vaccenic acid does not. Valid IEP showing
      differential fatty acid regulation.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:20508999
        supporting_text: >-
          gene expression of CPT I, hydroxyacyl-CoA dehydrogenase and
          hydroxymethylglutaryl-CoA synthase was at least 100% increased
- term:
    id: GO:0070542
    label: response to fatty acid
  evidence_type: IEP
  original_reference_id: PMID:10796071
  review:
    summary: >-
      PMID:10796071 shows 3-thia fatty acids increase Hmgcs2 activity,
      protein, and mRNA in rat liver. Valid IEP showing fatty acid
      regulation of ketogenesis.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:10796071
        supporting_text: >-
          Hepatic mitochondrial carnitine palmitoyltransferase (CPT) -II
          and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase
          activities, immunodetectable proteins, and mRNA levels increased
          in parallel
- term:
    id: GO:0071385
    label: cellular response to glucocorticoid stimulus
  evidence_type: IEP
  original_reference_id: PMID:9798904
  review:
    summary: >-
      PMID:9798904 shows hydrocortisone causes a 4-fold increase in
      Hmgcs2 mRNA in neonatal cortical astrocytes and meningeal
      fibroblasts. Valid IEP. Note this contrasts with the dexamethasone
      effect in suckling rat liver (PMID:9546617), indicating tissue-
      specific glucocorticoid responses.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:9798904
        supporting_text: >-
          glucocorticoid hydrocortisone effects a selective fourfold
          increase in mHS mRNA abundances in both neonatal meningeal
          fibroblasts and neonatal cortical astrocytes
- term:
    id: GO:0007584
    label: response to nutrient
  evidence_type: IEP
  original_reference_id: PMID:17103110
  review:
    summary: >-
      PMID:17103110 shows chronic dietary quercetin upregulates Hmgcs2
      in rat lung. Valid IEP showing nutrient (flavonoid) regulation
      of fatty acid catabolism genes.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:17103110
        supporting_text: >-
          fatty acid catabolism pathways, like beta-oxidation and
          ketogenesis, are up-regulated by the long-term quercetin
          intervention
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEP
  original_reference_id: PMID:15107969
  review:
    summary: >-
      PMID:15107969 shows phenobarbital treatment decreases Hmgcs2 mRNA
      in rat liver. Valid IEP.
    action: KEEP_AS_NON_CORE
    supported_by:
      - reference_id: PMID:15107969
        supporting_text: >-
          it was only weakly observed after the repeated PB treatments,
          presumably owing to a decrease in HMG-CoA synthase mRNA content
- term:
    id: GO:0043434
    label: response to peptide hormone
  evidence_type: IEP
  original_reference_id: PMID:12027802
  review:
    summary: >-
      PMID:12027802 demonstrates insulin (a peptide hormone) represses
      Hmgcs2 via FKHRL1. This is a more general version of the insulin
      response annotation already present. Redundant with GO:0032869.
    action: KEEP_AS_NON_CORE
    reason: Redundant with the more specific insulin response annotation.
    supported_by:
      - reference_id: PMID:12027802
        supporting_text: >-
          insulin rapidly inhibiting the expression of the mitochondrial
          3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2)
          gene, which is a key control site of ketogenesis
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: TAS
  original_reference_id: PMID:8097464
  review:
    summary: >-
      PMID:8097464 characterizes the gene structure and confirms
      liver-specific expression and multihormonal regulation. TAS for
      the enzymatic function. Consistent with IDA evidence.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:8097464
        supporting_text: >-
          Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA)
          synthase, a liver-specific enzyme, is a constituent of the
          HMG-CoA cycle responsible for ketone-body synthesis
- term:
    id: GO:0046951
    label: ketone body biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:8097464
  review:
    summary: >-
      PMID:8097464 describes Hmgcs2 as a constituent of the HMG-CoA
      cycle responsible for ketone-body synthesis. Valid TAS.
    action: ACCEPT
    supported_by:
      - reference_id: PMID:8097464
        supporting_text: >-
          a liver-specific enzyme, is a constituent of the HMG-CoA cycle
          responsible for ketone-body synthesis
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to
    orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: GO_REF:0000121
  title: RGD ISO annotations to rat from other mammalian species
  findings: []
- id: PMID:1967579
  title: Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase
    in vivo by decreasing the extent of succinylation of the enzyme.
  findings:
    - statement: Glucagon activates Hmgcs2 by lowering succinyl-CoA and reducing
        enzyme succinylation from ~40% to <10%.
      supporting_text: >-
        glucagon increases the activity of HMG-CoA synthase by lowering the
        concentration of succinyl-CoA and thus decreasing the extent of
        succinylation of the enzyme
- id: PMID:1971108
  title: Rat mitochondrial and cytosolic 3-hydroxy-3-methylglutaryl-CoA synthases
    are encoded by two different genes.
  findings:
    - statement: Rat mitochondrial HMG-CoA synthase is encoded by a separate gene
        from the cytosolic isoform, with a 37-residue mitochondrial targeting
        peptide.
      supporting_text: >-
        The expression product of the cDNA in Escherichia coli has HMG-CoA
        synthase activity
- id: PMID:7902069
  title: Regulation of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase
    protein by starvation, fat feeding, and diabetes.
  findings:
    - statement: Hmgcs2 protein increases with cAMP, dexamethasone, starvation, fat
        feeding, and diabetes; decreases with insulin and refeeding.
      supporting_text: >-
        The amount of mitochondrial HMG-CoA synthase protein rapidly increased
        in response to cyclic AMP, dexamethasone, starvation, fat feeding, and
        diabetes, whereas it was decreased by insulin and refeeding
- id: PMID:7911291
  title: Effect of squalene synthase inhibition on the expression of hepatic
    cholesterol biosynthetic enzymes, LDL receptor, and cholesterol 7 alpha
    hydroxylase.
  findings: []
- id: PMID:8097464
  title: The rat mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A-synthase gene
    contains elements that mediate its multihormonal regulation and tissue
    specificity.
  findings:
    - statement: The Hmgcs2 gene spans at least 24 kbp with 10 exons, and the
        proximal promoter contains liver-specific enhancers and cis-elements for
        multihormonal regulation.
      supporting_text: >-
        a liver-specific enzyme, is a constituent of the HMG-CoA cycle
        responsible for ketone-body synthesis
- id: PMID:8099282
  title: Developmental changes in mitochondrial 3-hydroxy-3-methylglutaryl-CoA
    synthase gene expression in rat liver, intestine and kidney.
  findings:
    - statement: Hmgcs2 is expressed in liver, intestine, and kidney of suckling
        rats with postnatal induction, disappearing from intestine and kidney
        upon weaning to high-carbohydrate diet.
      supporting_text: >-
        Kidney-cortex mitochondria from suckling rats were able to produce low
        amounts of ketone bodies from oleate
- id: PMID:8100835
  title: Vanadate treatment restores the expression of genes for key enzymes in the
    glucose and ketone bodies metabolism in the liver of diabetic rats.
  findings:
    - statement: Vanadate (insulin mimetic) normalizes the diabetes-induced
        increase in Hmgcs2 expression.
      supporting_text: >-
        The increase in the expression of the mitochondrial
        3-hydroxy-3-methylglutaryl-CoA synthase (HMGCoAS) gene, the key
        regulatory enzyme in the ketone bodies production pathway, observed
        in diabetic rats was also blocked by vanadate
- id: PMID:8620869
  title: The expression of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A
    synthase in neonatal rat intestine and liver is under transcriptional control.
  findings:
    - statement: Hmgcs2 expression in neonatal intestine and liver is
        transcriptionally regulated, with expression in enterocytes and
        mitochondrial (not cytosolic) localization of the protein.
      supporting_text: >-
        hepatic pre-mRNA of mitochondrial HOMeGlt-CoA synthase from suckling
        rats follows a pattern of expression identical to that of mature hepatic
        mRNA
- id: PMID:9025717
  title: Post-transcriptional induction of beta 1-adrenergic receptor by retinoic
    acid, but not triiodothyronine, in C6 glioma cells expressing thyroid hormone
    receptors.
  findings:
    - statement: T3 induces mitochondrial HMG-CoA synthase expression in C6 glioma
        cells expressing thyroid hormone receptor alpha 1.
      supporting_text: >-
        Cells expressing TR alpha 1, but not wild-type cells, were responsive
        to T3 as shown by increased expression of mitochrondrial
        hydroxymethylglutaryl CoA synthase after T3 exposure
- id: PMID:9143333
  title: The effect of fasting/refeeding and insulin treatment on the expression of
    the regulatory genes of ketogenesis in intestine and liver of suckling rats.
  findings:
    - statement: Insulin decreases Hmgcs2 activity and mRNA in suckling rat liver
        and intestine. Hmgcs2 correlates better with ketogenic rate than CPT I.
      supporting_text: >-
        the ketogenic rate correlated better to mit. HMG-CoA synthase than CPT
        I, and liver was the main organ regulating ketogenesis
- id: PMID:9546617
  title: The effect of dexamethasone treatment on the expression of the regulatory
    genes of ketogenesis in intestine and liver of suckling rats.
  findings:
    - statement: Dexamethasone decreases Hmgcs2 activity in suckling rat liver and
        intestine.
      supporting_text: >-
        In liver the mRNA levels and activity of both CPT I and mit. HMG-CoA
        synthase decreased
- id: PMID:9798904
  title: Hormonal regulation of the mRNA encoding the ketogenic enzyme mitochondrial
    3-hydroxy-3-methylglutaryl-CoA synthase in neonatal primary cultures of cortical
    astrocytes and meningeal fibroblasts.
  findings:
    - statement: Hydrocortisone causes 4-fold increase in Hmgcs2 mRNA in neonatal
        meningeal fibroblasts and cortical astrocytes.
      supporting_text: >-
        glucocorticoid hydrocortisone effects a selective fourfold increase in
        mHS mRNA abundances
- id: PMID:10357839
  title: Atypical expression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA
    synthase in subcutaneous adipose tissue of male rats.
  findings:
    - statement: Hmgcs2 is atypically expressed in subcutaneous adipose tissue in a
        testosterone-dependent, sex-specific, and age-dependent manner.
      supporting_text: >-
        The expression of mtHMG-CoA synthase is suppressed in SC fat pads of
        castrated male rats whereas treatment of castrated rats with testosterone
        restores a normal level of expression
- id: PMID:10796071
  title: Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase and carnitine
    palmitoyltransferase II as potential control sites for ketogenesis during
    mitochondrion and peroxisome proliferation.
  findings:
    - statement: 3-thia fatty acids increase Hmgcs2 activity, protein, and mRNA,
        suggesting it retains control over ketogenesis when CPT-I is bypassed.
      supporting_text: >-
        Hepatic mitochondrial carnitine palmitoyltransferase (CPT) -II and
        3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase activities,
        immunodetectable proteins, and mRNA levels increased in parallel
- id: PMID:11323196
  title: Cholesterol biosynthesis regulation and protein changes in rat liver
    following treatment with fluvastatin.
  findings:
    - statement: Fluvastatin induces compensatory upregulation of cholesterol
        biosynthesis pathway enzymes including HMG-CoA synthase.
      supporting_text: >-
        Major effects were evident in the cholesterol biosynthesis pathway
        including the induction of enzymes upstream and downstream of the
        target enzyme HMG CoA reductase
- id: PMID:11517196
  title: Opposite effect of prolactin and prostaglandin F(2 alpha) on the expression
    of luteal genes as revealed by rat cDNA expression array.
  findings:
    - statement: PGF2alpha inhibits HMG-CoA synthase expression in rat corpus
        luteum.
      supporting_text: >-
        It also inhibited genes involved in estradiol (P-450(AROM)) and
        cholesterol biosynthesis (HMG-CoA synthase)
- id: PMID:11551854
  title: Effects of fatty acids and growth hormone on liver fatty acid binding
    protein and PPARalpha in rat liver.
  findings:
    - statement: Dietary triglycerides increase Hmgcs2 mRNA only in the presence of
        growth hormone.
      supporting_text: >-
        Dietary triglycerides increased mitochondrial hydroxymethylglutaryl-CoA
        synthase mRNA only in the presence of GH
- id: PMID:11578593
  title: Analysis of genes differentially expressed in astrocytes stimulated with
    lipopolysaccharide using cDNA arrays.
  findings:
    - statement: Hmgcs2 is upregulated in LPS-stimulated astrocytes.
      supporting_text: >-
        mitochondrial hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase),
        aldehyde dehydrogenase 2, macrophage inflammatory protein 1 (MIP-1)
        and neurotensin receptor 2
- id: PMID:12027802
  title: 'Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA
    synthase gene by insulin: the role of the forkhead transcription factor FKHRL1.'
  findings:
    - statement: Insulin represses HMGCS2 via FKHRL1/FOXO3a-mediated transcriptional
        inhibition.
      supporting_text: >-
        insulin rapidly inhibiting the expression of the mitochondrial
        3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene
- id: PMID:12399220
  title: Impaired ketogenesis is a major mechanism for disturbed hepatic fatty acid
    metabolism in rats with long-term cholestasis and after relief of biliary
    obstruction.
  findings:
    - statement: Hmgcs2 is the rate-limiting factor in ketogenesis; its reduced
        expression is the major cause of impaired ketogenesis in cholestasis.
      supporting_text: >-
        reduced activity of HMG-CoA synthase is the major factor
- id: PMID:14686922
  title: Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic
    mucosa is modulated by bacterial species.
  findings:
    - statement: Butyrate-producing bacteria (Clostridium paraputrificum) restore
        colonic Hmgcs2 expression in germ-free rats.
      supporting_text: >-
        the intestinal flora, through butyrate production, could control the
        expression of colonic mHMGCoA synthase
- id: PMID:15107969
  title: Molecular mechanism investigation of phenobarbital-induced serum cholesterol
    elevation in rat livers by microarray analysis.
  findings:
    - statement: Phenobarbital decreases Hmgcs2 mRNA in rat liver.
      supporting_text: >-
        it was only weakly observed after the repeated PB treatments,
        presumably owing to a decrease in HMG-CoA synthase mRNA content
- id: PMID:16216487
  title: Differential action of 13-HPODE on PPARalpha downstream genes in rat Fao
    and human HepG2 hepatoma cell lines.
  findings:
    - statement: 13-HPODE (linoleic acid oxidation product) activates PPARalpha in
        rat hepatoma cells.
      supporting_text: >-
        no remarkable induction of the PPARalpha target genes ACO, CPT1A,
        mitochondrial HMG-CoA synthase and delta9-desaturase was observed
- id: PMID:16962226
  title: Restraint stress alters the duodenal expression of genes important for
    lipid metabolism in rat.
  findings:
    - statement: Restraint stress upregulates Hmgcs2 in rat duodenum, likely
        mediated by glucocorticoids.
      supporting_text: >-
        immobilization preferentially stimulated the expression of genes related
        to lipid metabolism, including genes encoding mitochondrial HMG-CoA
        synthase
- id: PMID:17103110
  title: Chronic quercetin exposure affects fatty acid catabolism in rat lung.
  findings:
    - statement: Chronic dietary quercetin upregulates Hmgcs2 in rat lung.
      supporting_text: >-
        Up-regulation of genes (Hmgcs2, Ech1, Acox1, Pcca, Lpl and Acaa2) was
        verified and confirmed by quantitative real time PCR
- id: PMID:17964421
  title: Effects of 4-hydroxynonenal on mitochondrial 3-hydroxy-3-methylglutaryl
    (HMG-CoA) synthase.
  findings:
    - statement: Chronic ethanol increases 4-HNE adduct on Hmgcs2, with
        compensatory protein increase.
      supporting_text: >-
        ethanol consumption increases the formation of a 4-HNE adduct with
        mitochondrial HMG-CoA synthase
- id: PMID:17971398
  title: Identification of palmitoylated mitochondrial proteins using a bio-orthogonal
    azido-palmitate analogue.
  findings:
    - statement: Hmgcs2 is palmitoylated in the mitochondrial matrix.
      supporting_text: >-
        confirmed the palmitoylation of newly identified mitochondrial
        3-hydroxy-3-methylglutaryl-CoA synthase
- id: PMID:20508999
  title: Dissimilar properties of vaccenic versus elaidic acid in beta-oxidation
    activities and gene regulation in rat liver cells.
  findings:
    - statement: Elaidic acid increases Hmgcs2 gene expression >100% in rat
        hepatocytes.
      supporting_text: >-
        gene expression of CPT I, hydroxyacyl-CoA dehydrogenase and
        hydroxymethylglutaryl-CoA synthase was at least 100% increased
- id: PMID:22673903
  title: Quantitative maps of protein phosphorylation sites across 14 different rat
    organs and tissues.
  findings:
    - statement: Phosphorylation at Ser-440 and Ser-477 identified by mass
        spectrometry.
      supporting_text: >-
        we present the broadest tissue catalogue of phosphoproteins to date,
        covering 31,480 phosphorylation sites on 7,280 proteins quantified
        across 14 rat organs and tissues
core_functions:
  - molecular_function:
      id: GO:0004421
      label: hydroxymethylglutaryl-CoA synthase activity
    directly_involved_in:
      - id: GO:0046951
        label: ketone body biosynthetic process
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    description: >-
      Hmgcs2 catalyzes the Claisen condensation of acetyl-CoA with
      acetoacetyl-CoA to form HMG-CoA in the mitochondrial matrix. This
      is the committed and rate-limiting step of ketogenesis. The product
      HMG-CoA is cleaved by HMG-CoA lyase to yield acetoacetate, the
      first ketone body. The enzyme is regulated post-translationally
      by succinylation (inhibitory, reversed by SIRT5) and
      transcriptionally by the fed-fasted axis (insulin represses via
      FOXO3a; glucagon activates via cAMP/desuccinylation). Expressed
      primarily in liver, with developmental expression in intestine and
      kidney.
    supported_by:
      - reference_id: PMID:1971108
        supporting_text: >-
          The expression product of the cDNA in Escherichia coli has
          HMG-CoA synthase activity
      - reference_id: PMID:1967579
        supporting_text: >-
          glucagon increases the activity of HMG-CoA synthase by lowering
          the concentration of succinyl-CoA
      - reference_id: PMID:12399220
        supporting_text: >-
          reduced activity of HMG-CoA synthase is the major factor
suggested_questions:
  - question: Does the palmitoylation of Hmgcs2 (identified in PMID:17971398)
      regulate its enzymatic activity or localization in vivo?
  - question: What is the physiological significance of Hmgcs2 expression in the
      stromal vascular fraction of subcutaneous adipose tissue?
    experts:
      - Pegorier JP
      - Thumelin S
  - question: How do the tissue-specific glucocorticoid effects on Hmgcs2
      (stimulatory in astrocytes, inhibitory in suckling liver) arise
      mechanistically?
    experts:
      - Cullingford TE
      - Hegardt FG
suggested_experiments:
  - hypothesis: Palmitoylation of Hmgcs2 at specific cysteine residues inhibits
      enzymatic activity similar to succinylation.
    description: Site-directed mutagenesis of candidate palmitoylation sites on
      Hmgcs2, followed by in vitro activity assays and palmitoylation status
      assessment, to determine whether palmitoylation directly modulates
      catalytic activity.
  - hypothesis: Hmgcs2 expression in subcutaneous adipose stromal cells represents
      a local ketogenic capacity for paracrine signaling.
    description: Isolate stromal vascular fraction from male rat subcutaneous
      adipose tissue, measure ketone body production rates, and assess
      whether ketone bodies affect nearby adipocyte differentiation or
      lipolysis.
  - description: Comparative proteomics of Hmgcs2 post-translational
      modifications (succinylation, acetylation, palmitoylation,
      phosphorylation) under fed, fasted, and diabetic conditions to
      build an integrated map of activity regulation.