{"id":"363a92d1-a454-53e6-a130-5cb03ba3daf1","stable_key":"e0ea2d6a-7429-5e9f-b774-41e5e3288da3:e-sig-insig-depletion-hmgcr-turnover","predicate":"prevents-tocotrienol-stimulated","statement":"Combined RNAi against INSIG1 and INSIG2 abolished gamma- and delta-tocotrienol-stimulated degradation of endogenous HMG-CoA reductase in sterol-depleted SV-589 fibroblasts supplied with 10 mM mevalonate.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"45c09839-0119-5760-934c-630117f7bdd7","mechanism_event_label":"Removing both INSIG regulators prevented these tocotrienols from accelerating loss of the reductase protein in this cell experiment.","subject":{"id":"52813bd3-4f0b-5f11-8e11-6a46b8516bc8","slug":"insig1-insig2-depletion","display_name":"Combined INSIG1 and INSIG2 depletion","entity_type_key":"cellular_process"},"object":{"id":"a5fb755e-0e91-56aa-abd6-d52f10a2033b","slug":"hmgcr-protein-degradation","display_name":"HMG-CoA reductase protein degradation","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"45c09839-0119-5760-934c-630117f7bdd7","stable_key":"e0ea2d6a-7429-5e9f-b774-41e5e3288da3:e-sig-insig-depletion-hmgcr-turnover-event","event_type":"biochemical_relationship","label":"Removing both INSIG regulators prevented these tocotrienols from accelerating loss of the reductase protein in this cell experiment.","description":"Combined RNAi against INSIG1 and INSIG2 abolished gamma- and delta-tocotrienol-stimulated degradation of endogenous HMG-CoA reductase in sterol-depleted SV-589 fibroblasts supplied with 10 mM mevalonate.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"10f91f6e-93c6-5ac9-a2cc-29e2bd83fa16","slug":"insig1","display_name":"Insulin-induced gene 1 protein (INSIG1)","entity_type_key":"protein"},"role":"depleted regulator","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"a051b0a5-ab34-5c27-99bf-d1635082355d","slug":"insig2","display_name":"Insulin-induced gene 2 protein (INSIG2)","entity_type_key":"protein"},"role":"depleted regulator","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"56c5cd15-b521-587d-a063-1cfd03644b46","slug":"delta-tocotrienol","display_name":"Delta-tocotrienol","entity_type_key":"small_molecule"},"role":"test compound","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"27fc7c66-efe2-57b6-988b-560bb242182d","slug":"gamma-tocotrienol","display_name":"Gamma-tocotrienol","entity_type_key":"small_molecule"},"role":"test compound","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"a8b5e5e1-b5b5-551d-8fd4-72f7b45de78a","slug":"hmgcr","display_name":"HMG-CoA reductase (HMGCR)","entity_type_key":"protein"},"role":"protein undergoing turnover","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"52813bd3-4f0b-5f11-8e11-6a46b8516bc8","slug":"insig1-insig2-depletion","display_name":"Combined INSIG1 and INSIG2 depletion","entity_type_key":"cellular_process"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""},{"entity":{"id":"a5fb755e-0e91-56aa-abd6-d52f10a2033b","slug":"hmgcr-protein-degradation","display_name":"HMG-CoA reductase protein degradation","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":6,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"cross_nutrient","value_text":"false","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Combined INSIG1/INSIG2 RNA interference in immortalized human SV-589 fibroblasts","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Sterol depletion 16 h; gamma- or delta-tocotrienol plus 10 mM mevalonate for 5 h; tocotrienol concentration not retrieved from the accessible Figure 3 text.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Combined knockdown establishes a machinery requirement in this model, not the unique role of either INSIG isoform or nutritional deficiency. 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Does not quantify viability or predict supplement benefit.\nexposure: Sterol depletion 16 h; gamma- or delta-tocotrienol plus 10 mM mevalonate for 5 h; tocotrienol concentration not retrieved from the accessible Figure 3 text.\ncross_nutrient: false\n[song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. (2006). https://pubmed.ncbi.nlm.nih.gov/16831864/ DOI: 10.1074/jbc.m605575200","model_system":"Combined INSIG1/INSIG2 RNA interference in immortalized human SV-589 fibroblasts","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. 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