{"doi":"10.3389/fendo.2024.1491965","title":"Editorial: Hepatocyte nuclear factor 4 alpha – new insights into an old receptor","abstract":"Hepatocyte nuclear factor 4 alpha (HNF4α), cloned over 30 years ago based on its ability to bind a couple of DNA elements in liver-specific genes, is now considered to be the master regulator of liver-specific transcription. HNF4α is also expressed in several other tissues, including intestines, kidney, stomach and pancreas, and is linked to several human diseases (Figure 1). As a member of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors, HNF4α has two highly conserved domains for DNA binding (DBD) and ligand binding (LBD) and binds DNA as a homodimer. This Research Topic contains four reviews and three original research articles covering some of the most important areas of research on HNF4α and its paralog HNF4γ. The original research article by Deans et al uses the exon swap mice to elucidate the role of P2-versus P1-HNF4α isoforms in the adult liver. P2-HNF4α was originally identified in an embryonic cancer cell line but is now known to be expressed in the normal adult liver during periods of fasting, high fat diet and alcohol-associated liver disease, as well as liver cancer. The authors use multiple 'omics approaches to show not only that HNF4α is one of the most highly expressed transcription factors in the adult liver but also that the hundreds of genes uniquely regulated by P2-HNF4α (including several cytochrome P450 genes) are consistent with a role in metabolism. They show that the differential gene expression is likely due to interactions with coregulators rather than alterations in DNA or chromatin binding and propose a potential role for the HNF4α isoforms in the circadian switch between carbohydrate and lipid metabolism.The review by Vemuri et al focusses on the intestines which express both P1-and P2-HNF4α as well as HNF4γ. HNF4α binds DNA as a homodimer and cannot heterodimerize with other NRs, with the exception of HNF4γ. Like HNF4α, HNF4γ has been shown to bind fatty acids although, as with HNF4α, the role of ligand binding in receptor function is not clear. Both HNF4 genes play a key role in intestinal maturation, differentiation and regeneration as well as stem cell renewal (via fatty acid oxidation) and barrier function, allowing for one paralog to compensate for the loss of the other. HNF4α intersects with the immune system in multiple ways and, along with HNF4γ, protects against a chronic inflammatory state in the gut. Both HNF4 genes are implicated in the intestinal entry of SARS-CoV2 via regulation of the Ace2 and Tmprss2 genes in the intestinal epithelium. Interestingly, three distinct high fat diets have also been shown to alter the expression of these (and other) COVID-related genes as well as Hnf4a in the mouse intestines (1).The original article by Kotulkar et al explores the interaction between HNF4α and the protooncogene c-Myc in liver regeneration after partial hepatectomy. Deletion of HNF4α increases the expression of c-Myc and cyclin D1 (Ccnd1) while the double knockout of HNF4α and c-Myc decreases hepatocyte proliferation demonstrating that HNF4α is critical for both termination of liver regeneration and survival after partial hepatectomy. Another intriguing observation is the emergence of HNF4α+ hepatocytes in HNF4α knockout mice, presumably from the cholangiocytes. This work highlights a role for HNF4α in regulating cell proliferation, as well as basic metabolism.Critical areas of future HNF4 research include the role of: i) HNF4α in the intersection between cell metabolism and proliferation; ii) the different splice variants and the factors that regulate splicing as well as the alternate HNF4A promoters; iii) post translational modifications (PMTs) in HNF4 and how they can be impacted by SNPs in the human population (2); iv) HNF4α versus HNF4γ in the intestines (and other tissues), including homo-versus heterodimers and their interaction with the microbiome (3); v) the incredible diversity of HNF4 and other NR binding motifs and how those might be impacted ","journal":"Frontiers in Endocrinology","year":2024,"id":487367,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":277669,"name":"Udayan Apte","orcid":"0000-0002-6741-7164","position":1,"is_corresponding":false},{"id":338660,"name":"Poonamjot Deol","orcid":null,"position":2,"is_corresponding":false},{"id":338021,"name":"Frances M. Sladek","orcid":"0000-0001-8346-8474","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T02:08:06.013846Z","pmid":"39387053","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}