HNF4α isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4α is expressed at ZT9 and ZT21 in the normal adult liver and orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions. We demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in females. Exon swap mice expressing only P2- HNF4α exhibit subtle differences in circadian gene regulation and disruption of the clock increases expression of P2-HNF4α. Taken together, we propose that the highly conserved two-promoter structure of the Hnfa gene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.

Diet High in Soybean Oil Increases Susceptibility to Colitis in Mice

SUMMARYSoybean oil (SO), the most prevalent cooking oil in the United States, consists primarily of linoleic acid (LA, C18:2 omega-6), a polyunsaturated fatty acid positively linked to the development of ulcerative colitis (UC) in humans. Here, we show that dietary SO increases intestinal epithelial barrier permeability and susceptibility to colitis in mice. It also disrupts the balance of isoforms encoded by the UC susceptibility gene Hepatocyte Nuclear Factor 4α (HNF4α), which in turn impacts barrier function and IBD susceptibility. The SO diet causes gut dysbiosis, including an increased abundance of an adherent, invasive Escherichia coli (AIEC) which can use LA as a carbon source. Metabolomic analysis indicates that gut bacteria and the SO diet can alter levels of LA and its oxylipin and endocannabinoid metabolites in the gut. Our results suggest that an SO-enriched diet increases susceptibility to colitis due to effects on intestinal HNF4α, microbiota and LA metabolites.

Hepatocyte nuclear factor 4α and cancer-related cell signaling pathways: a promising insight into cancer treatment

Hepatocyte nuclear factor 4α (HNF4α), a member of the nuclear receptor superfamily, is described as a protein that binds to the promoters of specific genes. It controls the expression of functional genes and is also involved in the regulation of numerous cellular processes. A large number of studies have demonstrated that HNF4α is involved in many human malignancies. Abnormal expression of HNF4α is emerging as a critical factor in cancer cell proliferation, apoptosis, invasion, dedifferentiation, and metastasis. In this review, we present emerging insights into the roles of HNF4α in the occurrence, progression, and treatment of cancer; reveal various mechanisms of HNF4α in cancer (e.g., the Wnt/β-catenin, nuclear factor-κB, signal transducer and activator of transcription 3, and transforming growth factor β signaling pathways); and highlight potential clinical uses of HNF4α as a biomarker and therapeutic target for cancer.

Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics

Hepatocyte nuclear factor 4α (HNF4α) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4α gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure–activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4α activity in a low micromolar range. These compounds demonstrate the druggability of HNF4α and thus provide a starting point for medicinal chemistry as well as an early tool for chemogenomics.