{"id":"d083f2fc-0831-5f93-b696-38d5ee9d2bef","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-metformin-cholestasis","predicate":"worsens_in_model","statement":"In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis and worsened liver injury.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"223a9299-7d8c-5d23-b089-8227a873e548","mechanism_event_label":"In an already cholestatic liver the same mechanism made things worse.","subject":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"object":{"id":"e2727eda-60ff-55ff-b82d-86e114b886a3","slug":"cholestatic-liver-injury","display_name":"Cholestatic liver injury in the 2014 mouse model","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"223a9299-7d8c-5d23-b089-8227a873e548","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-metformin-cholestasis-event","event_type":"biochemical_relationship","label":"In an already cholestatic liver the same mechanism made things worse.","description":"In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis and worsened liver injury.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"6c968572-2908-5ee5-b48d-76d6767269d1","slug":"bile-acid-homeostasis","display_name":"Bile acid homeostasis","entity_type_key":"cellular_process"},"role":"disturbed_process","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"e2727eda-60ff-55ff-b82d-86e114b886a3","slug":"cholestatic-liver-injury","display_name":"Cholestatic liver injury in the 2014 mouse model","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/metformin-research/24531544.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad\", \"start_char\": 0, \"end_char\": 1358, \"text_sha256\": \"9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Metformin and other AMPK activators with FXR agonists","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.","comparator":null,"unit":null,"notes":"","entity":{"slug":"metformin","display_name":"Metformin","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human cells and mouse","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"In an already cholestatic liver the same mechanism made things worse.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Liver and intestine","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"47b0887c-f907-5448-b361-c4ca7014566b","evidence_kind":"source_excerpt","locator":"Lines 1022-1033","start_line":1022,"end_line":1033,"excerpt":"### metformin-metformin-cholestasis\nIn a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis and worsened liver injury.\nCondition category: normal\nnutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.\nplain_language: In an already cholestatic liver the same mechanism made things worse.\norganism: Human cells and mouse\ntissue_or_cell_type: Liver and intestine\nexperimental_model: Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model\nlimitations: An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes.\nexposure: Metformin and other AMPK activators with FXR agonists\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/24531544.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad\", \"start_char\": 0, \"end_char\": 1358, \"text_sha256\": \"9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad\"}\n[metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815","model_system":"Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. 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