ArticleProceedings of the National Academy of Sciences of the United States of America1997
The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 149 papers, 1 of them a synthesis that pooled it.
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Who cites it
149 citing papers in PubMed, 1 synthesis or guideline pooled it, 413 citations in OpenAlex.
- DNA methylation and type 2 diabetes: a systematic review.Clinical epigenetics · 2024Pooled it
- The Genetic Landscape of Diabetes Mellitus: Lessons from Monogenic and Polygenic Forms.Life (Basel, Switzerland) · 2026Review
- Exploring the prediction model and core genes for coronary artery disease in non-obese steatotic liver disease patients.Frontiers in medicine · 2026Article
- Article
- Bridging pancreatic and hepatic development: overlapping genes and their role in diabetes.Cellular & molecular biology letters · 2025Review
- Genetic and clinical characteristics of children with mody: insights into novel HNF4A variants and genotype-phenotype correlation.Irish journal of medical science · 2025Article
- Rheb1 as a novel β-cell regulator connecting mTORC1, AMPK, and NOTCH1 pathways for efficient diabetes therapy.World journal of diabetes · 2025Article
- Identification of IL-34 and Slc7al as potential key regulators in MASLD progression through epigenomic profiling.Epigenomics · 2025Article
- Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM.Biomolecules · 2025Review
- Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2.ACS pharmacology & translational science · 2025Article
- Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- TIFAB modulates metabolic pathways in KMT2A::MLLT3-induced AML through HNF4A.Blood advances · 2025Article
- MODY PDX1Frontiers in endocrinology · 2025Article
- Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects.Human molecular genetics · 2024Article
- Transcriptional regulation of metabolism in the intestinal epithelium.American journal of physiology. Gastrointestinal and liver physiology · 2023Review
- Parallel CRISPR-Cas9 screens identify mechanisms of PLIN2 and lipid droplet regulation.Developmental cell · 2023Article
- NEUROD1 reinforces endocrine cell fate acquisition in pancreatic development.Nature communications · 2023Article
- Expanding the p.(Arg85Trp) Variant-Specific Phenotype of HNF4A: Features of Glycogen Storage Disease, Liver Cirrhosis, Impaired Mitochondrial Function, and Glomerular Changes.Molecular syndromology · 2023Article
- HNF4α isoforms: the fraternal twin master regulators of liver function.Frontiers in endocrinology · 2023Review
- Multiple roles and regulatory mechanisms of the transcription factor HNF4 in the intestine.Frontiers in endocrinology · 2023Review
89 more citing papers are in PubMed but not listed here.
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2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatocyte nuclear factor 4alpha (HNF4alpha) plays a critical role in regulating the expression of many genes essential for normal functioning of liver, gut, kidney, and pancreatic islets. A nonsense mutation (Q268X) in exon 7 of the HNF4alpha gene is responsible for an autosomal dominant, early-onset form of non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young; gene named MODY1). Although this mutation is predicted to delete 187 C-terminal amino acids of the HNF4alpha protein the molecular mechanism by which it causes diabetes is unknown. To address this, we first studied the functional properties of the MODY1 mutant protein. We show that it has lost its transcriptional transactivation activity, fails to dimerize and bind DNA, implying that the MODY1 phenotype is because of a loss of HNF4alpha function. The effect of loss of function on HNF4alpha target gene expression was investigated further in embryonic stem cells, which are amenable to genetic manipulation and can be induced to form visceral endoderm. Because the visceral endoderm shares many properties with the liver and pancreatic beta-cells, including expression of genes for glucose transport and metabolism, it offers an ideal system to investigate HNF4-dependent gene regulation in glucose homeostasis. By exploiting this system we have identified several genes encoding components of the glucose-dependent insulin secretion pathway whose expression is dependent upon HNF4alpha. These include glucose transporter 2, and the glycolytic enzymes aldolase B and glyceraldehyde-3-phosphate dehydrogenase, and liver pyruvate kinase. In addition we have found that expression of the fatty acid binding proteins and cellular retinol binding protein also are down-regulated in the absence of HNF4alpha. These data provide direct evidence that HNF4alpha is critical for regulating glucose transport and glycolysis and in doing so is crucial for maintaining glucose homeostasis.
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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.