Human farnesoid X receptor / NR1H4

evidence_span

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experimental_model

Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model

exposure

Metformin and other AMPK activators with FXR agonists

limitations

An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human cells and mouse

plain_language

The energy sensor directly switches down the bile-acid receptor.

primary_references

[metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815

tissue_or_cell_type

Liver and intestine

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 996–1007

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model · source_derived_draft · unverified_draft

### metformin-ampk-fxr AMPK interacted with FXR in the cytoplasm and phosphorylated it in its hinge domain, inhibiting FXR transcriptional activity and preventing coactivator recruitment. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The energy sensor directly switches down the bile-acid receptor. organism: Human cells and mouse tissue_or_cell_type: Liver and intestine experimental_model: Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model limitations: An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes. exposure: Metformin and other AMPK activators with FXR agonists evidence_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"} [metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815

duration

Not applicable

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

High-throughput compound library screen, FXR ligand-binding domain crystal structure

exposure

Ivermectin complexed with the FXR ligand-binding domain

limitations

The authors describe FXR as the first mammalian protein targeted by ivermectin with high selectivity, which is a claim about selectivity among mammalian targets rather than about potency.

organism

High-throughput compound library screen, FXR ligand-binding domain crystal structure

plain_language

Ivermectin bound the farnesoid X receptor ligand-binding domain and induced its transcriptional activity, with a crystal structure showing a distinct binding mode and an expanded ligand-binding pocket.

primary_references

The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. (2013). https://pubmed.ncbi.nlm.nih.gov/23728580/ DOI: 10.1038/ncomms2924

route

In vitro and structural

tissue

Nuclear receptor transcriptional activity and coregulator recruitment

Ivermectin: mechanism of action across parasite, host barrier and mammalian targets (2026-09-22) · lines 123–132

Original AI-assisted curation of sixteen primary studies resolved by PubMed title search and cross-checked against live PubMed metadata. Study-specific citations, concentrations, negative findings and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## ivermectin-fxr-ligand Ivermectin bound the farnesoid X receptor ligand-binding domain and induced its transcriptional activity, with a crystal structure showing a distinct binding mode and an expanded ligand-binding pocket. Model/species: High-throughput compound library screen, FXR ligand-binding domain crystal structure Tissue/system: Nuclear receptor transcriptional activity and coregulator recruitment Exposure: Ivermectin complexed with the FXR ligand-binding domain Route: In vitro and structural Duration: Not applicable Limits: The authors describe FXR as the first mammalian protein targeted by ivermectin with high selectivity, which is a claim about selectivity among mammalian targets rather than about potency. Primary reference: The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. (2013). https://pubmed.ncbi.nlm.nih.gov/23728580/ DOI: 10.1038/ncomms2924 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

cross_nutrient

Hepatic heme synthesis; ALAS1 is distinct from erythroid ALAS2.

experimental_model

Primary human hepatocytes and human liver slices; reporter assays

exposure

Experimental bile-acid or FXR-agonist treatment

limitations

No B6 manipulation; this is regulation of the pathway, not proof of a B6 rescue effect.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

The liver heme pathway has its own regulation in addition to its cofactor needs.

primary_references

[b6-alas1-2007] Regulation of human liver delta-aminolevulinic acid synthase by bile acids. (2007). https://pubmed.ncbi.nlm.nih.gov/17975826/ DOI: 10.1002/hep.21879

tissue_or_cell_type

Primary human hepatocytes and human liver slices

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 835–846

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary human hepatocytes and human liver slices; reporter assays · source_derived_draft · unverified_draft

### b6-met-alas1-fxr Chenodeoxycholic acid increased ALAS1 mRNA and enzyme activity in primary human hepatocytes and liver slices through an FXR-linked regulatory mechanism. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The liver heme pathway has its own regulation in addition to its cofactor needs. organism: Homo sapiens tissue_or_cell_type: Primary human hepatocytes and human liver slices experimental_model: Primary human hepatocytes and human liver slices; reporter assays limitations: No B6 manipulation; this is regulation of the pathway, not proof of a B6 rescue effect. cross_nutrient: Hepatic heme synthesis; ALAS1 is distinct from erythroid ALAS2. exposure: Experimental bile-acid or FXR-agonist treatment [b6-alas1-2007] Regulation of human liver delta-aminolevulinic acid synthase by bile acids. (2007). https://pubmed.ncbi.nlm.nih.gov/17975826/ DOI: 10.1002/hep.21879

evidence_span

{"source_cache": "artifacts/metformin-research/30397356.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf", "start_char": 0, "end_char": 1433, "text_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf"}

experimental_model

Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments

exposure

Three days of metformin in treatment-naive people; B. fragilis colonisation in high-fat-diet mice

limitations

A three-day human exposure with a mouse causal test. GUDCA is identified as an intestinal FXR antagonist; whole-body FXR biology is not claimed.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human and mouse

plain_language

That bile acid switches off a gut receptor that controls metabolism.

primary_references

[metformin-p30397356] Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. (2018). https://pubmed.ncbi.nlm.nih.gov/30397356/ DOI: 10.1038/s41591-018-0222-4

tissue_or_cell_type

Gut lumen and intestinal epithelium

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 879–890

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments · source_derived_draft · unverified_draft

### metformin-gudca-fxr GUDCA was identified as an intestinal FXR antagonist, and these changes were accompanied by inhibition of intestinal FXR signalling. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: That bile acid switches off a gut receptor that controls metabolism. organism: Human and mouse tissue_or_cell_type: Gut lumen and intestinal epithelium experimental_model: Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments limitations: A three-day human exposure with a mouse causal test. GUDCA is identified as an intestinal FXR antagonist; whole-body FXR biology is not claimed. exposure: Three days of metformin in treatment-naive people; B. fragilis colonisation in high-fat-diet mice evidence_span: {"source_cache": "artifacts/metformin-research/30397356.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf", "start_char": 0, "end_char": 1433, "text_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf"} [metformin-p30397356] Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. (2018). https://pubmed.ncbi.nlm.nih.gov/30397356/ DOI: 10.1038/s41591-018-0222-4

duration

Not stated here

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Wild-type and FXR-null mice

exposure

Ivermectin treatment

limitations

The null-mouse comparison attributes the metabolic effect to FXR; it does not establish a dose relevant to human antiparasitic use.

organism

Wild-type and FXR-null mice

plain_language

Ivermectin decreased serum glucose and cholesterol in wild-type mice but not in FXR-null mice.

primary_references

The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. (2013). https://pubmed.ncbi.nlm.nih.gov/23728580/ DOI: 10.1038/ncomms2924

route

In vivo

tissue

Serum glucose and cholesterol

Ivermectin: mechanism of action across parasite, host barrier and mammalian targets (2026-09-22) · lines 134–143

Original AI-assisted curation of sixteen primary studies resolved by PubMed title search and cross-checked against live PubMed metadata. Study-specific citations, concentrations, negative findings and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## ivermectin-lowers-glucose-through-fxr Ivermectin decreased serum glucose and cholesterol in wild-type mice but not in FXR-null mice. Model/species: Wild-type and FXR-null mice Tissue/system: Serum glucose and cholesterol Exposure: Ivermectin treatment Route: In vivo Duration: Not stated here Limits: The null-mouse comparison attributes the metabolic effect to FXR; it does not establish a dose relevant to human antiparasitic use. Primary reference: The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. (2013). https://pubmed.ncbi.nlm.nih.gov/23728580/ DOI: 10.1038/ncomms2924 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.