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Mouse Knockout Models of Biliary Epithelial Cell Formation and Disease
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Hnf4 is a member of the nuclear-receptor superfamily of transcription factors is pivotal for hepatocyte differentiation. Homozygous inactivation of the Hnf4 gene in mouse results in early embryonic lethality, with yolk-sac defects before gastrulation.48 Specifically, many mature hepatocyte genes fail to be activated in conditional mutants, including those that encode apolipoproteins, serum factors and metabolic enzymes, and two transcriptional regulators, Hnflalpha and PXR (also known as Nrli2; nuclear-receptor subfamily 1, group I, member 2) were affected, indicating that Hnf4 truly elicits the terminal phase of hepatocyte differentiation.44,47,48
Congenital hyperinsulinism
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Christopher A. Behr, Stephen E. Dolgin
While mutations in the genes affecting the KATP channel are implicated in 80%–90% of the identifiable causes of CH, the other 10%–20% of cases are caused by mutations in one of six different genes affecting other processes. The GLUD1 (encoding glutamate dehydrogenase enzyme), CGK (encoding glucokinase), HADH (encoding short-chain L-3-hydroxyacyl-CoA dehydrogenase), SLC16A1 (encoding a monocarboxylate transporter), and UCP2 (encoding UCP2 protein) genes all affect the ATP/ADP ratio within the beta cells, which determines the status of the KATP channel [4, 23–26]. Likewise, a transcription factor defect in the HNF4A (hepatocyte nuclear factor 4 alpha) gene has been shown to cause neonatal hyperinsulinemia [27]. All of these mutations result in the diffuse, usually mild, form of CH, and all are diazoxide responsive (except GCK, which has variable diazoxide responsiveness) (Figure 39.2).
The Genetics of Diabetes and Its Complications in Older Adults
Published in Medha N. Munshi, Lewis A. Lipsitz, Geriatric Diabetes, 2007
Jeremy D. Walston, Kristi D. Silver
The hepatocyte nuclear factor 4 alpha (HNF4α) is a β cell transcription factor that regulates expression of genes involved with glucose metabolism and insulin secretion. The HNF4α gene localizes to chromosome 20q13, a region that has been linked to T2DM in a number of genome wide linkage studies (55–58). There are several isoforms for the gene as a result of alternate splicing and transcription from two different promoters. The predominant transcription start site in pancreatic β cells is the P2 promoter.
A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism
Published in Drug Metabolism Reviews, 2022
Jianxin Yang, Xue Bai, Guiqin Liu, Xiangyang Li
Hepatocyte nuclear factors (HNFs) are a class of transcription factors (TFs) of the Pit-Oct-Unc (POU) homeodomain family that regulate liver-specific gene expression. According to the different regions corresponding to functional domains of HNFs, four families are classified: namely HNF1, HNF3, HNF4, and HNF6 (Lau et al. 2018). HNF1 has two subtypes: HNF1α and HNF1β. HNF4, a member of the orphan nuclear receptor family, has two subtypes: HNF4α and HNF4γ. Both HNF4α and HNF1α can bind to DNA in the form of dimers and regulate nutrient and exogenous metabolism as well as cell homeostasis, proliferation, and apoptosis. The HNF4α and HNF1α genes were initially identified as mutated genes associated with maturity-onset diabetes of the young (MODY) 1 and MODY3; patients with both mutated genes may exhibit more severe diabetes symptoms (Forlani et al. 2010). Subsequently, the roles of HNF4α and HNF1α in various metabolic diseases, liver diseases, cancer, and other diseases and their potential as drug targets have gradually emerged.
Therapeutic Potential of HNF4α in End-stage Liver Disease
Published in Organogenesis, 2021
Ricardo Diaz-Aragon, Michael C. Coard, Sriram Amirneni, Lanuza Faccioli, Nils Haep, Michelle R. Malizio, Takashi Motomura, Zehra N. Kocas-Kilicarslan, Alina Ostrowska, Rodrigo M. Florentino, Carla Frau
Since alternative treatment options for ESLD are urgently needed, different approaches to treat ESLD are currently under investigation.7,8 Moroni et al.8 confirmed the safety of autologous macrophage transplantation for potential treatment of cirrhosis and other fibrotic diseases. One of the most promising methods is the exploration of liver-enriched transcription factors (LETFs). LETFs, along with transactivation factors, have a great influence on the maintenance of liver-specific gene transcription.9 Liu et al.10 reported the initial hypothesis, which described the role of hepatocyte-specific transcription factors in the development of ESLD.10,11 Interestingly, the expression of hepatocyte nuclear factor 4-alpha (HNF4α) was found to be directly correlated to liver disease in humans.10,12 HNF4α is a transcription factor that plays an important role in liver morphogenesis and maintenance of proper hepatocyte function in a mature liver.13–15 Most liver diseases have been associated with altered HNF4α expression, isoform ratios, and localization.16 Therefore, many studies have indicated that HNF4α may potentially be a target gene for the regression of fibrosis and cirrhosis.17,18 This review touches upon the functions and regulation of HNF4α in a healthy mature liver, as well as the role of HNF4α in liver disease, particularly in ESLD. Implementation of HNF4α as a key therapeutic target for future ESLD treatment is discussed as well.
Emerging technologies in pediatrics: the paradigm of neonatal diabetes mellitus
Published in Critical Reviews in Clinical Laboratory Sciences, 2020
Nicolas C. Nicolaides, Christina Kanaka-Gantenbein, Nektaria Papadopoulou-Marketou, Amalia Sertedaki, George P. Chrousos, Ioannis Papassotiriou
Since then, several studies using targeted NGS have reported novel mutations in genes associated with NDM. Anderson de la Liana et al. described a case of a very low birth weight neonate who developed diabetes mellitus 13 days after birth. The authors used targeted NGS of 323 diabetes-associated genes and found a novel mutation (p.Pro190Leu) in HNF4 and a p.Glu23Lys mutation in KCNJ11 [77]. Kylat et al. identified a missense mutation in KCNJ11 (c.685G > A) in two cases with transient NDM who were then transitioned from insulin to sulfonylureas [78]. Interestingly, a novel NEUROG3 mutation, p.Q4*, was recently identified in a patient with NDM, malabsorptive diarrhea, neurointestinal dysplasia and other atypical clinical manifestations. The same mutation was found in another family member who presented with abnormalities in the central nervous system, thyroid gland and intrahepatic biliary tract [79].