ArticleCell death & disease2021
Liver fat storage is controlled by HNF4α through induction of lipophagy and is reversed by a potent HNF4α agonist.
Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 38 citations in OpenAlex.
- Lipophagy and lipid droplets in neurodegeneration.Trends in pharmacological sciences · 2026Review
- A whole-animal phenotypic drug screen identifies suppressors of atherogenic lipoproteins.eLife · 2026Article
- Stomach at the crossroads: nuclear receptor signaling at the interface between what we are and what we eat.Physiological reviews · 2026Review
- Hepatocyte HIF2α Downregulates the Urea Cycle Through Suppression of HNF4α.Gastro hep advances · 2026Article
- Transomic analysis reveals DNA methylation and transcription factor roles in obese liver protein expression.NPJ systems biology and applications · 2025Article
- Hepatocyte nuclear factors dynamically regulate triglyceride metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: Mechanisms and implications.World journal of hepatology · 2025Review
- Orphan Nuclear Receptors in Metabolic Dysfunction-associated Steatotic Liver Disease Development.Journal of clinical and translational hepatology · 2025Review
- 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
- Exploring the Lesser-Known Bioactive Natural Products of Plant Species of the GenusPlants (Basel, Switzerland) · 2025Review
- Identification ofFrontiers in microbiology · 2025Article
- Structure-based identification of HNF4α agonists: Rosmarinic acid as a promising candidate for NAFLD treatment.Computational and structural biotechnology journal · 2025Article
- Three new species ofMycoKeys · 2025Article
- HNF4α contributes to hepatic CAR dysfunction in polymicrobial sepsis.Frontiers in immunology · 2025Article
- A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.EMBO molecular medicine · 2024Article
- Cross-Species Comparative DNA Methylation Reveals Novel Insights into Complex Trait Genetics among Cattle, Sheep, and Goats.Molecular biology and evolution · 2024Article
- The Role of Nuclear Receptors in the Pathogenesis and Treatment of Non-alcoholic Fatty Liver Disease.International journal of biological sciences · 2024Review
- Hepatocyte nuclear factor 4α mediated quinolinate phosphoribosylltransferase (QPRT) expression in the kidney facilitates resilience against acute kidney injury.Kidney international · 2023Article
- HNF4α is possibly the missing link between epithelial-mesenchymal transition and Warburg effect during hepatocarcinogenesis.Cancer science · 2023Article
- Conserved roles for Hnf4 family transcription factors in zebrafish development and intestinal function.Genetics · 2022Article
- A review of the phytochemical and pharmacological properties of Amauroderma rugosum.The Kaohsiung journal of medical sciences · 2022Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We report the discovery of strong HNF4α agonists and their use to uncover a previously unknown pathway by which HNF4α controls the level of fat storage in the liver. This involves the induction of lipophagy by dihydroceramides, the synthesis and secretion of which is controlled by genes induced by HNF4α. The HNF4α activators are N-trans caffeoyltyramine (NCT) and N-trans feruloyltyramine (NFT), which are structurally related to the known drugs alverine and benfluorex, which we previously showed to be weak HNF4α activators. In vitro, NCT and NFT induced fat clearance from palmitate-loaded cells. In DIO mice, NCT led to recovery of hepatic HNF4α expression and reduction of steatosis. Mechanistically, increased dihydroceramide production and action downstream of HNF4α occurred through increased expression of HNF4α downstream genes, including SPNS2 and CYP26A1. NCT was completely nontoxic at the highest dose administered and so is a strong candidate for an NAFLD therapeutic.
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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.