ArticlePloS one2009
Identification of an endogenous ligand bound to a native orphan nuclear receptor.
Article in PloS one, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
131 citing papers in PubMed, 204 citations in OpenAlex.
- Ligand-dependent reprogramming of HNF4A expression and function suppresses multistep hepatocarcinogenesis.Molecular therapy. Oncology · 2026Article
- The role of HNF4α in adenocarcinoma.Biochemical Society transactions · 2026Review
- Silencing lipid catabolism determines longevity in response to fasting.Nature communications · 2026Article
- P2-HNF4α alters linoleic acid metabolism and mitigates soybean oil-induced obesity: role for oxylipins.Journal of lipid research · 2025Article
- Article
- Hepatocyte Nuclear Factor 4 Alpha: A Key Regulator of Liver Disease Pathology and Haemostatic Disorders.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Crosstalk Between Dietary Fatty Acids and MicroRNAs in the Regulation of Hepatic ApoB-Containing Lipoprotein Synthesis in Humans.International journal of molecular sciences · 2025Review
- Gastric Adenocarcinomas with CDX2 Induction Show Higher Frequency ofJournal of clinical medicine · 2024Article
- A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.EMBO molecular medicine · 2024Article
- Impact of various high fat diets on gene expression and the microbiome across the mouse intestines.Scientific reports · 2023Article
- Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy.The Journal of clinical investigation · 2023Article
- Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β (International journal of molecular sciences · 2023Article
- HNF4α in Hepatocyte Health and Disease.Seminars in liver disease · 2023Review
- Brain nuclear receptors and cardiovascular function.Cell & bioscience · 2023Review
- The protein architecture and allosteric landscape of HNF4α.Frontiers in endocrinology · 2023Review
- HNF4α isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver.Frontiers in endocrinology · 2023Article
- Multiple roles and regulatory mechanisms of the transcription factor HNF4 in the intestine.Frontiers in endocrinology · 2023Review
- HNF4α isoforms: the fraternal twin master regulators of liver function.Frontiers in endocrinology · 2023Review
- Structural insights into the HNF4 biology.Frontiers in endocrinology · 2023Review
- Review
71 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Orphan nuclear receptors have been instrumental in identifying novel signaling pathways and therapeutic targets. However, identification of ligands for these receptors has often been based on random compound screens or other biased approaches. As a result, it remains unclear in many cases if the reported ligands are the true endogenous ligands,--i.e., the ligand that is bound to the receptor in an unperturbed in vivo setting. Technical limitations have limited our ability to identify ligands based on this rigorous definition. The orphan receptor hepatocyte nuclear factor 4 alpha (HNF4alpha) is a key regulator of many metabolic pathways and linked to several diseases including diabetes, atherosclerosis, hemophilia and cancer. Here we utilize an affinity isolation/mass-spectrometry (AIMS) approach to demonstrate that HNF4alpha is selectively occupied by linoleic acid (LA, C18:2omega6) in mammalian cells and in the liver of fed mice. Receptor occupancy is dramatically reduced in the fasted state and in a receptor carrying a mutation derived from patients with Maturity Onset Diabetes of the Young 1 (MODY1). Interestingly, however, ligand occupancy does not appear to have a significant effect on HNF4alpha transcriptional activity, as evidenced by genome-wide expression profiling in cells derived from human colon. We also use AIMS to show that LA binding is reversible in intact cells, indicating that HNF4alpha could be a viable drug target. This study establishes a general method to identify true endogenous ligands for nuclear receptors (and other lipid binding proteins), independent of transcriptional function, and to track in vivo receptor occupancy under physiologically relevant conditions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.