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1
Ozsu, Elif, Filiz Mine Cizmecioglu, Gul Yesiltepe Mutlu, Aysegul Bute Yuksel, Mursel Calıskan, Ahmet Yesilyurt, and Sukru Hatun. "Maturity Onset Diabetes of the Young due to Glucokinase, HNF1-A, HNF1-B, and HNF4-A Mutations in a Cohort of Turkish Children Diagnosed as Type 1 Diabetes Mellitus." Hormone Research in Paediatrics 90, no. 4 (2018): 257–65. http://dx.doi.org/10.1159/000494431.
Анотація:
Background/Aims: Maturity onset diabetes of the young (MODY) is a rare condition often misdiagnosed as type 1 diabetes (T1D). The purposes of this study were: to identify any patients followed in a large Turkish cohort as T1D, with an atypical natural history, who may in fact have MODY, and to define the criteria which would indicate patients with likely MODY as early as possible after presentation to allow prompt genetic testing. Methods: Urinary C-peptide/creatinine ratio (UCPCR) was studied in 152 patients having a diagnosis of T1D for at least 3 years. Those with a UCPCR ≥0.2 nmol/mmol were selected for genetic analysis of the Glucokinase (GCK), Hepatocyte nuclear factor 1a (HNF1A), Hepatocyte nuclear factor 4a (HNF4A), and Hepatocyte nuclear factor 1b (HNF1B) genes. This UCPCR cut-off was used because of the reported high sensitivity and specificity. Cases were also evaluated using a MODY probability calculator. Results: Twenty-three patients from 152 participants (15.1%) had a UCPCR indicating persistent insulin reserve. The mean age ± SD of the patients was 13.6 ± 3.6 years (range 8.30–21.6). Of these 23, two (8.7%) were found to have a mutation, one with HNF4A and one with HNF1B mutation. No mutations were detected in the GCK or HNF1A genes. Conclusion: In Turkish children with a diagnosis of T1D but who have persistent insulin reserve 3 years after diagnosis, up to 9% may have a genetic mutation indicating a diagnosis of MODY.
2
Au, Wo-Shing, Liwei Lu, Chung-Man Yeung, Ching-Chiu Liu, Oscar G. Wong, Lihui Lai, Hsiang-fu Kung, and Marie C. Lin. "Hepatocyte nuclear factor 1 binding element within the promoter of microsomal triglyceride transfer protein (MTTP) gene is crucial for MTTP basal expression and insulin responsiveness." Journal of Molecular Endocrinology 41, no. 4 (August 12, 2008): 229–38. http://dx.doi.org/10.1677/jme-08-0080.
Анотація:
Insulin inhibits the transcription of the microsomal triglyceride transfer protein (MTTP), which plays a pivotal role in lipoprotein assembly and secretion. Here, we provide evidence that a hepatocyte nuclear factor 1 binding element (HNF1A element) within the MTTP promoter serves as a novel negative insulin-responsive element. Deletion/mutation mapping of the MTTP gene promoter identified a modified HNF1A element that is crucial to the negative insulin effect. Chimeric promoter containing this HNF1A element and minimal TEAD1 promoter also responded negatively toward insulin treatment. Gel shift assay demonstrated that HNF1A but not HNF1B binds to this element. Enforced expression of HNF1A was sufficient to reconstitute the negative insulin responsiveness of MTTP promoter in TM4SF1 myocytes that are HNF1A negative. Furthermore, replacing this element with consensus HNF1A element preserved the negative insulin response, suggesting that negative insulin responsiveness is a generic characteristic of HNF1A element. Given that many genes implicated in diabetes contain HNF1A element, the potential regulation of these genes by insulin via HNF1A element may provide important clues for the manifestation and treatment of diabetic metabolic syndromes.
3
Tudor, Lucija, Marcela Konjevod, Gordana Nedic Erjavec, Matea Nikolac Perkovic, Suzana Uzun, Oliver Kozumplik, Vlatka Zoldos, Gordan Lauc, Dubravka Svob Strac та Nela Pivac. "Genetic and Epigenetic Association of Hepatocyte Nuclear Factor-1α with Glycosylation in Post-Traumatic Stress Disorder". Genes 13, № 6 (14 червня 2022): 1063. http://dx.doi.org/10.3390/genes13061063.
Анотація:
Post-traumatic stress disorder (PTSD) is a complex trauma-related disorder, the etiology and underlying molecular mechanisms of which are still unclear and probably involve different (epi)genetic and environmental factors. Protein N-glycosylation is a common post-translational modification that has been associated with several pathophysiological states, including inflammation and PTSD. Hepatocyte nuclear factor-1α (HNF1A) is a transcriptional regulator of many genes involved in the inflammatory processes, and it has been identified as master regulator of plasma protein glycosylation. The aim of this study was to determine the association between N-glycan levels in plasma and immunoglobulin G, methylation at four CpG positions in the HNF1A gene, HNF1A antisense RNA 1 (HNF1A-AS1), rs7953249 and HNF1A rs735396 polymorphisms in a total of 555 PTSD and control subjects. We found significant association of rs7953249 and rs735396 polymorphisms, as well as HNF1A gene methylation at the CpG3 site, with highly branched, galactosylated and sialyated plasma N-glycans, mostly in patients with PTSD. HNF1A-AS1 rs7953249 polymorphism was also associated with PTSD; however, none of the polymorphisms were associated with HNF1A gene methylation. These results indicate a possible regulatory role of the investigated HNF1A polymorphisms with respect to the abundance of complex plasma N-glycans previously associated with proinflammatory response, which could contribute to the clinical manifestation of PTSD and its comorbidities.
4
Bonzo, Jessica A., Andrew D. Patterson, Kristopher W. Krausz та Frank J. Gonzalez. "Metabolomics Identifies Novel Hnf1α-Dependent Physiological Pathways in Vivo". Molecular Endocrinology 24, № 12 (1 грудня 2010): 2343–55. http://dx.doi.org/10.1210/me.2010-0130.
Анотація:
Abstract Mutations in the HNF1A gene cause maturity-onset diabetes of the young type 3, one of the most common genetic causes of non-insulin-dependent (type 2) diabetes mellitus. Although the whole-body Hnf1a-null mouse recapitulates the low insulin levels and high blood glucose observed in human maturity-onset diabetes of the young type 3 patients, these mice also suffer from Laron dwarfism and aminoaciduria, suggesting a role for hepatocyte nuclear factor 1α (Hnf1α) in pathophysiologies distinct from non-insulin-dependent (type 2) diabetes mellitus. In an effort to identify pathways associated with inactivation of Hnf1α, an ultraperformance liquid chromatography coupled to mass spectrometry-based metabolomics study was conducted on urine samples from wild-type and Hnf1a-null mice. An increase in phenylalanine metabolites is in agreement with the known regulation of the phenylalanine hydroxylase gene by Hnf1α. This metabolomic approach also identified urinary biomarkers for three tissue-specific dysfunctions previously unassociated with Hnf1α function. 1) Elevated indolelactate coupled to decreased xanthurenic acid also indicated defects in the indole and kynurenine pathways of tryptophan metabolism, respectively. 2) An increase in the neutral amino acid proline in the urine of Hnf1a-null mice correlated with loss of renal apical membrane transporters of the Slc6a family. 3) Further investigation into the mechanism of aldosterone increase revealed an overactive adrenal gland in Hnf1a-null mice possibly due to inhibition of negative feedback regulation. Although the phenotype of the Hnf1a-null mouse is complex, metabolomics has opened the door to investigation of several physiological systems in which Hnf1α may be a critical regulatory component.
5
Chen, Yinling, Jianxin Jia, Qing Zhao, Yuxian Zhang, Bingkun Huang, Likun Wang, Juanjuan Tian, Caoxin Huang, Mingyu Li та Xuejun Li. "Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress". International Journal of Molecular Sciences 23, № 21 (27 жовтня 2022): 13022. http://dx.doi.org/10.3390/ijms232113022.
Анотація:
Heterozygous variants in the hepatocyte nuclear factor 1a (HNF1a) cause MODY3 (maturity-onset diabetes of the young, type 3). In this study, we found a case of novel HNF1a p.Gln125* (HNF1a-Q125ter) variant clinically. However, the molecular mechanism linking the new HNF1a variant to impaired islet β-cell function remains unclear. Firstly, a similar HNF1a-Q125ter variant in zebrafish (hnf1a+/−) was generated by CRISPR/Cas9. We further crossed hnf1a+/− with several zebrafish reporter lines to investigate pancreatic β-cell function. Next, we introduced HNF1a-Q125ter and HNF1a shRNA plasmids into the Ins-1 cell line and elucidated the molecular mechanism. hnf1a+/− zebrafish significantly decreased the β-cell number, insulin expression, and secretion. Moreover, β cells in hnf1a+/− dilated ER lumen and increased the levels of ER stress markers. Similar ER-stress phenomena were observed in an HNF1a-Q125ter-transfected Ins-1 cell. Follow-up investigations demonstrated that HNF1a-Q125ter induced ER stress through activating the PERK/eIF2a/ATF4 signaling pathway. Our study found a novel loss-of-function HNF1a-Q125ter variant which induced β-cell dysfunction by activating ER stress via the PERK/eIF2a/ATF4 signaling pathway.
6
Liu, Rui, Hanning Liu, Haiyong Gu, Xiao Teng, Yu Nie, Zhou Zhou, Yan Zhao, Shengshou Hu, and Zhe Zheng. "A Polymorphism inHepatocyte Nuclear Factor 1 Alpha,rs7310409, Is Associated with Left Main Coronary Artery Disease." Biochemistry Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/924105.
Анотація:
Coronary artery disease is the leading cause of mortality and morbidity in the world. Left main coronary artery disease (LMCAD) is a particularly severe phenotypic form of CAD and has a genetic basis. We hypothesized that some inflammation- and hyperhomocysteinemia-related gene polymorphisms may contribute to LMCAD susceptibility in a Chinese population. We studied the association between polymorphisms in the genes hepatocyte nuclear factor 1 alpha (HNF1A; rs7310409, G/A), C-reactive protein (rs1800947 and rs3093059 T/C), methylenetetrahydrofolate reductase (rs1801133, C/T), and methylenetetrahydrofolate dehydrogenase (rs1076991, A/G) in 402 LMCAD and 804 more peripheral CAD patients in a Chinese population. Genotyping was performed using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. When the HNF1A rs7310409 GG homozygote genotype was used as the reference group, both the individual, GA and AA, and combined GA/AA genotypes were associated with an increased risk of LMCAD. This single nucleotide polymorphism (rs7310409) is strongly associated with plasma CRP levels. In conclusion, the present study provides evidence that the HNF1A rs7310409 G/A functional polymorphism may contribute to the risk of LMCAD.
7
Demus, Daniel, Paulina A. Urbanowicz, Richard A. Gardner, Haiyang Wu, Agata Juszczak, Tamara Štambuk, Edita Pape Medvidović та ін. "Development of an exoglycosidase plate-based assay for detecting α1-3,4 fucosylation biomarker in individuals with HNF1A-MODY". Glycobiology 32, № 3 (25 жовтня 2021): 230–38. http://dx.doi.org/10.1093/glycob/cwab107.
Анотація:
Abstract Maturity-onset diabetes of the young due to hepatocyte nuclear factor-1 alpha variants (HNF1A-MODY) causes monogenic diabetes. Individuals carrying damaging variants in HNF1A show decreased levels of α1-3,4 fucosylation, as demonstrated on antennary fucosylation of blood plasma N-glycans. The excellent diagnostic performance of this glycan biomarker in blood plasma N-glycans of individuals with HNF1A-MODY has been demonstrated using liquid chromatography methods. Here, we have developed a high-throughput exoglycosidase plate-based assay to measure α1-3,4 fucosylation levels in blood plasma samples. The assay has been optimized and its validity tested using 1000 clinical samples from a cohort of individuals with young-adult onset diabetes including cases with HNF1A-MODY. The α1-3,4 fucosylation levels in blood plasma showed a good differentiating power in identifying cases with damaging HNF1A variants, as demonstrated by receiver operating characteristic curve analysis with the AUC values of 0.87 and 0.95. This study supports future development of a simple diagnostic test to measure this glycan biomarker for application in a clinical setting.
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Ma, Yumin, Siqian Gong, Xirui Wang, Xiaoling Cai, Xinhua Xiao, Weijun Gu, Jinkui Yang, et al. "New clinical screening strategy to distinguish HNF1A variant-induced diabetes from young early-onset type 2 diabetes in a Chinese population." BMJ Open Diabetes Research & Care 8, no. 1 (March 2020): e000745. http://dx.doi.org/10.1136/bmjdrc-2019-000745.
Анотація:
ObjectiveMaturity-onset diabetes of the young caused by hepatocyte nuclear factor-1 alpha (HNF1A) variants (HNF1A-MODY) is a common form of monogenetic diabetes. Although patients with HNF1A-MODY might specifically benefit from sulfonylurea treatment, available methods for screening this specific type of diabetes are not cost-effective. This study was designed to establish an optimized clinical strategy based on multiple biomarkers to distinguish patients with HNF1A-MODY from clinically diagnosed early-onset type 2 diabetes (EOD) for genetic testing in a Chinese population.Research design and methodsA case–control study including 125 non-related young patients with EOD and 15 probands with HNF1A-MODY (cohort 1) was conducted to evaluate reported biomarkers for HNF1A-MODY. A cut-off for the fasting insulin (Fins) level, the 97.5 percentile of 150 healthy subjects with normal components of metabolic syndrome (cohort 2), was used to filter out individuals with obvious insulin resistance (Fins <102 pmol/L). An optimized clinical screening strategy (HNF1A-CSS) was established, and its effectiveness was assessed in another group of 410 young patients with EOD (cohort 3).ResultsIn cohort 1, body mass index (BMI), serum high-density lipoprotein cholesterol (HDL-c) and high-sensitivity C reactive protein (hs-CRP) levels were confirmed to be useful for the differential diagnosis of HNF1A-MODY. In cohort 3, eight probands with HNF1A-MODY were identified. In cohort 3 and young relatives with HNF1A-MODY, meeting three of four criteria (BMI <28 kg/m2, hs-CRP <0.75 mg/L, Fins <102 pmol/L and HDL-c >1.12 mmol/L), the sensitivity and specificity of HNF1A-CSS were 100% and 69.3%, respectively. In the pooled analysis of all young patients, HNF1A-CSS displayed 90.5% sensitivity and 73.6% specificity for identifying patients with HNF1A-MODY among those with clinically diagnosed EOD.ConclusionOur HNF1A-CSS is useful for distinguishing patients with HNF1A-MODY from patients with EOD in a young Chinese population.
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Pace, Nikolai Paul, Christopher Rizzo, Alexia Abela, Mark Gruppetta, Stephen Fava, Alex Felice, and Josanne Vassallo. "Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family." Clinical Medicine Insights: Case Reports 12 (January 2019): 117954761983103. http://dx.doi.org/10.1177/1179547619831034.
Анотація:
The diagnosis of maturity onset diabetes of the young (MODY) is a challenging process in view of the extensive clinical and genetic heterogeneity of the disease. Mutations in the gene encoding hepatocyte nuclear factor 1α ( HNF1A) are responsible for most forms of monogenic diabetes in Northern European populations. Genetic analysis through a combination of whole exome sequencing and Sanger sequencing in three Maltese siblings and their father identified a rare duplication/frameshift mutation in exon 4 of HNF1A that lies within a known mutational hotspot in this gene. In this report, we provide the first description of an HNF1A-MODY3 phenotype in a Maltese family. The findings reported are relevant and new to a regional population, where the epidemiology of atypical diabetes has never been studied before. This report is of clinical interest as it highlights how monogenic diabetes can be misdiagnosed as either type 1, type 2, or gestational diabetes. It also reinforces the need for a better characterisation of monogenic diabetes in Mediterranean countries, particularly in island populations such as Malta with a high prevalence of diabetes.
10
Zhang, Chuanhui, Fei Xie, Ling Li, Cheng Zhang, Yong Zhang, Wantao Ying, Li Liu, Xuli Yan, Futao Yin, and Lianwen Zhang. "Hepatocyte nuclear factor 1 alpha (HNF1A) regulates transcription of O ‐GlcNAc transferase in a negative feedback mechanism." FEBS Letters 593, no. 10 (May 2019): 1050–60. http://dx.doi.org/10.1002/1873-3468.13381.
11
Gan, Hoong-Wei, Jayesh Mahendra Bhatt, Louise Denvir, Tabitha Randell, and Pooja Sachdev. "Monogenic diabetes mellitus in cystic fibrosis." Archives of Disease in Childhood 104, no. 9 (September 29, 2018): 887–89. http://dx.doi.org/10.1136/archdischild-2018-316141.
Анотація:
We present a non-consanguineous family of three siblings who presented with diabetes mellitus (DM), two of whom had genetically confirmed cystic fibrosis (CF), with one pancreatic-sufficient mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (ΔF508/R117H;IVS8-5T). A detailed history revealed family members from three successive generations diagnosed with ‘type 1’ or ‘type 2’ diabetes, leading to genetic investigations for monogenic DM. A heterozygous frameshift mutation in the hepatocyte nuclear factor 1 homeobox alpha (HNF1A) gene (c.404delA) was subsequently confirmed in all three siblings, which is known to cause monogenic diabetes and is exquisitely sensitive to sulfonylurea therapy. Following this diagnosis, both siblings with CF and HNF1A monogenic diabetes were started on gliclazide therapy, while their older brother who had been wrongly diagnosed with type 1 diabetes was switched from insulin to gliclazide, all with excellent therapeutic responses.
12
Malikova, Jana, Alba Kaci, Petra Dusatkova, Ingvild Aukrust, Janniche Torsvik, Klara Vesela, Pavla Dvorakova Kankova, Pål R. Njølstad, Stepanka Pruhova, and Lise Bjørkhaug. "Functional Analyses of HNF1A-MODY Variants Refine the Interpretation of Identified Sequence Variants." Journal of Clinical Endocrinology & Metabolism 105, no. 4 (February 4, 2020): e1377-e1386. http://dx.doi.org/10.1210/clinem/dgaa051.
Анотація:
Abstract Context While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. Objective We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. Design, Settings, and Participants We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). Results Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Phe215SerfsTer18, p.Gly253Arg, p.Leu383ArgfsTer3, p.Gly437Val, and p.Thr563HisfsTer85) exhibited significantly reduced transcriptional activity or DNA binding (< 40%) and were classified as (likely) pathogenic, 2/17 variants were (likely) benign and 3/17 remained of uncertain significance. Functional analyses allowed for the reclassification of 10/17 variants (59%). Diabetes treatment was improved in 20/29 (69%) carriers of (likely) pathogenic HNF1A variants. Conclusion Functional evaluation of the HNF1A variants is necessary to better predict the pathogenic effects and to improve the diagnostic interpretation and treatment, particularly in cases where the cosegregation or family history data are not available or where the phenotype is more diverse and overlaps with other types of diabetes.
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Jeeyavudeen, Mohammad Sadiq, Sarah R. Murray, and Mark W. J. Strachan. "Management of monogenic diabetes in pregnancy: A narrative review." World Journal of Diabetes 15, no. 1 (January 15, 2024): 15–23. http://dx.doi.org/10.4239/wjd.v15.i1.15.
Анотація:
Pregnancy in women with monogenic diabetes is potentially complex, with significant implications for both maternal and fetal health. Among these, maturity-onset diabetes of the young (MODY) stands out as a prevalent monogenic diabetes subtype frequently encountered in clinical practice. Each subtype of MODY requires a distinct approach tailored to the pregnancy, diverging from management strategies in non-pregnant individuals. Glucokinase MODY (GCK-MODY) typically does not require treatment outside of pregnancy, but special considerations arise when a woman with GCK-MODY becomes pregnant. The glycemic targets in GCK-MODY pregnancies are not exclusively dictated by the maternal/paternal MODY genotype but are also influenced by the genotype of the developing fetus. During pregnancy, the choice between sulfonylurea or insulin for treating hepatocyte nuclear factor 1-alpha (HNF1A)-MODY and HNF4A-MODY depends on the mother’s specific circumstances and the available expertise. Management of other rarer MODY subtypes is individualized, with decisions made on a case-by-case basis. Therefore, a collaborative approach involving expert diabetes and obstetric teams is crucial for the comprehensive management of MODY pregnancies.
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Nault, Jean Charles, and Jessica Zucman Rossi. "Molecular Classification of Hepatocellular Adenomas." International Journal of Hepatology 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/315947.
Анотація:
Hepatocellular adenomas (HCAs) are benign tumors developed in normal liver most frequently in women before menopause. HCAs lead to diagnostic pitfalls and several difficulties to assess the risk of malignant transformation in these young patients. Recent advances in basic knowledge have revealed a molecular classification related to risk factors, pathological features, and risk of transformation in hepatocellular carcinoma. Three major molecular pathways have been identified altered in specific HCA subgroups that are defined by either (1) inactivation of hepatocyte nuclear factor 1A (HNF1A) transcription factor, (2) activation of the WNT/β-catenin byCTNNB1mutations, or (3) activation of the IL6/STAT3 pathway by somatic mutation ofIL6ST,GNAS, orSTAT3. Here, we will review the different molecular classes of HCA.
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Ming-Qiang, Zhu, Dai Yang-Li, Huang Ke, Wu Wei, Fu Jun-Fen, Zou Chao-Chun, and Dong Guan-Ping. "Maturity onset diabetes of the young (MODY) in Chinese children: genes and clinical phenotypes." Journal of Pediatric Endocrinology and Metabolism 32, no. 7 (July 26, 2019): 759–65. http://dx.doi.org/10.1515/jpem-2018-0446.
Анотація:
Abstract Background To investigate the clinical and molecular characteristics of Chinese children with maturity onset diabetes of the young (MODY). Methods A total of 42 Chinese patients suspected MODY referred to our unit from 2014 to 2018 were enrolled. Mutational analysis of monogenic diabetes mellitus genes was performed by next-generation sequencing and confirmed by Sanger sequencing. Results There were 28 males (66.7%) and 14 females (33.3%) with a mean age of 9.49 ± 3.46 years (range, 1.4–15.3 years) and a mean birth weight of 3.38 ± 0.49 kg (range, 2.55–4.90 kg). Among these patients, 15 patients had polyuria, polydipsia or weight loss. Two patients (4.8%) were obese and six (14.3%) were overweight. Moreover, 13 patients (30.9%) had a family history of diabetes. Thirty variants were identified in 28 patients. Twenty-six variants in 25 patients were pathogenic or likely pathogenic genes (59.5%, 25/42), including 15 patients (60.0%, 15/25) with GCK mutation, four (16.0%, 4/25) with PAX4 mutation, three (12.0%, 3/25) with HNF4A mutation, one (4.0%, 1/25) with INS mutation, one (4.0%, 1/25) with NEUROD1 mutation and one (4.0%, 1/25) with HNF1A mutation. Nine mutations (36.0%, 9/25) were novel. There was no difference between mutation-suspected patients and MODY-confirmed patients except for a 2-h glucose increment in an oral glucose tolerance test (OGTT), while the GCK-MODY had lower glycated hemoglobin (HbA1c) and a significantly smaller 2-h glucose increment in an OGTT compared with transcription factor MODYs. The GCK-MODY was identified by incidental hyperglycemia without glycosuria. GCK-MODY without drug management and hepatocyte nuclear factor-1 alpha (HNF4A) or HNF1A-MODY with sulfonylurea therapy obtained good glucose controlling. Conclusions Mutation of the GCK gene is the most common in MODY patients in China followed by PAX4. The screening criteria can improve the cost-effectiveness of disease diagnosis and treatment. A precise molecular diagnosis would lead to optimal treatment of the patients.
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CARRIÈRE, Véronique, Michel LACASA та Monique ROUSSET. "Activity of hepatocyte nuclear factor 1α and hepatocyte nuclear factor 1β isoforms is differently affected by the inhibition of protein phosphatases 1/2A". Biochemical Journal 354, № 2 (22 лютого 2001): 301–8. http://dx.doi.org/10.1042/bj3540301.
Анотація:
Phosphorylation/dephosphorylation processes are known to control the activity of several transcription factors. The nutrition-dependent expression of sucrase–isomaltase and Na+/glucose co-transporter 1, two proteins implicated in the intestinal absorption of glucose, has been shown to be closely related to modifications of hepatocyte nuclear factor 1 (HNF1) activity. This study was conducted to determine whether phosphorylation/dephosphorylation processes could control HNF1 activity. We show that expression of the gene encoding sucrase–isomaltase is inhibited in the enterocytic Caco-2 clone TC7 by okadaic acid at a concentration that is known to inhibit protein phosphatases 1/2A and that does not affect cell viability. At the same concentration, phosphorylation of the HNF1α and HNF1β isoforms is greatly enhanced and their DNA-binding capacity is decreased. The phosphorylation state of HNF1β isoforms directly affects their DNA-binding capacity. In contrast, the decreased DNA-binding activity of the HNF1α isoforms, which was observed after the inhibition of protein phosphatases 1/2A, is due to a net decrease in their total cellular and nuclear amounts. Such an effect results from a decrease in both the HNF1α mRNA levels and the half-life of the protein. This is the first evidence for the implication of protein phosphatases 1/2A in the control of the activity of HNF1 isoforms. Moreover, these results emphasize a physiological role for the balance between phosphatases and kinases in the nutrition-dependent regulation of HNF1-controlled genes.
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Vashi, Neeti, Carolina Stryjecki, Jesus Peralta-Romero, Fernando Suarez, Jaime Gomez-Zamudio, Ana I. Burguete-Garcia, Miguel Cruz, and David Meyre. "Genetic markers of inflammation may not contribute to metabolic traits in Mexican children." PeerJ 4 (June 23, 2016): e2090. http://dx.doi.org/10.7717/peerj.2090.
Анотація:
Background:Low-grade chronic inflammation is a common feature of obesity and its cardio-metabolic complications. However, little is known about a possible causal role of inflammation in metabolic disorders. Mexico is among the countries with the highest obesity rates in the world and the admixed Mexican population is a relevant sample due to high levels of genetic diversity.Methods:Here, we studied 1,462 Mexican children recruited from Mexico City. Six genetic variants in five inflammation-related genes were genotyped: rs1137101 (leptin receptor (LEPR)), rs7305618 (hepatocyte nuclear factor 1 alpha (HNF1A)), rs1800629 (tumor necrosis factor alpha (TNFA)), rs1800896, rs1800871 (interleukin-10 (IL-10)), rs1862513 (resistin (RETN)). Ten continuous and eight binary traits were assessed. Linear and logistic regression models were used adjusting for age, sex, and recruitment centre.Results:We found that one SNP displayed a nominal evidence of association with a continuous trait: rs1800871 (IL-10) with LDL (beta = −0.068 ± 1.006, P = 0.01). Subsequently, we found one nominal association with a binary trait: rs7305618 (HNF1A) with family history of hypertension (odds-ratio = 1.389 [1.054–1.829], P = 0.02). However, no P-value passed the Bonferroni correction for multiple testing.Discussion:Our data in a Mexican children population are consistent with previous reports in European adults in failing to demonstrate an association between inflammation-associated single nucleotide polymorphisms (SNPs) and metabolic traits.
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Grzanka, Malgorzata, Bartlomiej Matejko, Magdalena Szopa, Beata Kiec-Wilk, Maciej T. Malecki, and Tomasz Klupa. "Assessment of Newly Proposed Clinical Criteria to IdentifyHNF1AMODY in Patients with an Initial Diagnosis of Type 1 or Type 2 Diabetes Mellitus." Advances in Medicine 2016 (2016): 1–3. http://dx.doi.org/10.1155/2016/4243784.
Анотація:
The most common form of maturity-onset diabetes of the young (MODY) is caused by mutations in the hepatocyte nuclear factor 1A (HNF1A) gene. However, mostHNF1Amutation-carriers are initially misdiagnosed with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus; hence, they often receive nonoptimal treatment. The aim of our study was to test newly proposed clinical criteria for the identification ofHNF1AMODY in patients with a diagnosis of T1DM or T2DM. To achieve this, the following criteria to preselect patients for screening were used: for T1DM: TDIR (total daily insulin requirement) > 0.3 IU of insulin/kg and the percentage of basal insulin > 30% of TDIR; for T2DM: sulphonylurea- (SU-) based oral treatment (monotherapy or combined with Metformin) > 15 years and BMI < 30 kg/m2. We reviewed the clinical data of 140 patients with T1DM and 524 clinically diagnosed with T2DM. On the basis of these criteria, we found aHNF1Amutation in 1 out of 2 individuals with a diagnosis of T1DM and 1 out of 11 selected individuals with a diagnosis of T2DM. We believe that the simplicity of the proposed criteria might prove useful in clinical practice, as an alternative to more time-consuming classical diagnostic techniques.
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Haddouche, Aini, Christine Bellanne‐Chantelot, Anne Rod, Luc Fournier, Laurence Chiche, Jean‐Francois Gautier, Jose Timsit, et al. "Liver adenomatosis in patients with hepatocyte nuclear factor‐1 alpha maturity onset diabetes of the young ( HNF1A ‐MODY): Clinical, radiological and pathological characteristics in a French series." Journal of Diabetes 12, no. 1 (July 10, 2019): 48–57. http://dx.doi.org/10.1111/1753-0407.12959.
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Holst, Stephanie, Jennifer Wilding, Kamila Koprowska, Yoann Rombouts, and Manfred Wuhrer. "N-Glycomic and Transcriptomic Changes Associated with CDX1 mRNA Expression in Colorectal Cancer Cell Lines." Cells 8, no. 3 (March 22, 2019): 273. http://dx.doi.org/10.3390/cells8030273.
Анотація:
The caudal-related homeobox protein 1 (CDX1) is a transcription factor, which is important in the development, differentiation, and homeostasis of the gut. Although the involvement of CDX genes in the regulation of the expression levels of a few glycosyltransferases has been shown, associations between glycosylation phenotypes and CDX1 mRNA expression have hitherto not been well studied. Triggered by our previous study, we here characterized the N-glycomic phenotype of 16 colon cancer cell lines, selected for their differential CDX1 mRNA expression levels. We found that high CDX1 mRNA expression associated with a higher degree of multi-fucosylation on N-glycans, which is in line with our previous results and was supported by up-regulated gene expression of fucosyltransferases involved in antenna fucosylation. Interestingly, hepatocyte nuclear factors (HNF)4A and HNF1A were, among others, positively associated with high CDX1 mRNA expression and have been previously proven to regulate antenna fucosylation. Besides fucosylation, we found that high CDX1 mRNA expression in cancer cell lines also associated with low levels of sialylation and galactosylation and high levels of bisection on N-glycans. Altogether, our data highlight a possible role of CDX1 in altering the N-glycosylation of colorectal cancer cells, which is a hallmark of tumor development.
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Griscelli, Frank, Hélène Ezanno, Mathis Soubeyrand, Olivier Feraud, Noufissa Oudrhiri, Amélie Bonnefond, Ali G. Turhan, Philippe Froguel, and Annelise Bennaceur-Griscelli. "Generation of an induced pluripotent stem cell (iPSC) line from a patient with maturity-onset diabetes of the young type 3 (MODY3) carrying a hepatocyte nuclear factor 1-alpha ( HNF1A ) mutation." Stem Cell Research 29 (May 2018): 56–59. http://dx.doi.org/10.1016/j.scr.2018.02.017.
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Østoft, Signe Harring, Jonatan Ising Bagger, Torben Hansen, Bolette Hartmann, Oluf Pedersen, Jens Juul Holst, Filip Krag Knop, and Tina Vilsbøll. "Postprandial incretin and islet hormone responses and dipeptidyl-peptidase 4 enzymatic activity in patients with maturity onset diabetes of the young." European Journal of Endocrinology 173, no. 2 (August 2015): 205–15. http://dx.doi.org/10.1530/eje-15-0070.
Анотація:
ObjectiveThe role of the incretin hormones in the pathophysiology of maturity onset diabetes of the young (MODY) is unclear.DesignWe studied the postprandial plasma responses of glucagon, incretin hormones (glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)) and dipeptidyl-peptidase 4 (DPP4) enzymatic activity in patients with glucokinase (GCK) diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A) diabetes (MODY3) as well as in matched healthy individuals (CTRLs).Subjects and methodsTen patients with MODY2 (mean age±s.e.m.43±5 years; BMI 24±2 kg/m2; fasting plasma glucose (FPG) 7.1±0.3 mmol/l: HbA1c 6.6±0.2%), ten patients with MODY3 (age 31±3 years; BMI 24±1 kg/m2; FPG 8.9±0.8 mmol/l; HbA1c 7.0±0.3%) and ten CTRLs (age 40±5 years; BMI 24±1 kg/m2; FPG 5.1±0.1 mmol/l; HbA1c 5.3±0.1%) were examined with a liquid test meal.ResultsAll of the groups exhibited similar baseline values of glucagon (MODY2: 7±1 pmol/l; MODY3: 6±1 pmol/l; CTRLs: 8±2 pmol/l,P=0.787), but patients with MODY3 exhibited postprandial hyperglucagonaemia (area under the curve (AUC) 838±108 min×pmol/l) as compared to CTRLs (182±176 min×pmol/l,P=0.005) and tended to have a greater response than did patients with MODY2 (410±154 min×pmol/l,P=0.063). Similar peak concentrations and AUCs for plasma GIP and plasma GLP1 were observed across the groups. Increased fasting DPP4 activity was seen in patients with MODY3 (17.7±1.2 mU/ml) vs CTRLs (13.6±0.8 mU/ml,P=0.011), but the amount of activity was similar to that in patients with MODY2 (15.0±0.7 mU/ml,P=0.133).ConclusionThe pathophysiology of MODY3 includes exaggerated postprandial glucagon responses and increased fasting DPP4 enzymatic activity but normal postprandial incretin responses both in patients with MODY2 and in patients with MODY3.
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PONTOGLIO, MARCO. "Hepatocyte Nuclear Factor 1, a Transcription Factor at the Crossroads of Glucose Homeostasis." Journal of the American Society of Nephrology 11, suppl 2 (November 2000): S140—S143. http://dx.doi.org/10.1681/asn.v11suppl_2s140.
Анотація:
Abstract. Hepatocyte nuclear factor 1 (HNF1) is a transcription factor involved in the regulation of a large set of hepatic genes, including albumin, β-fibrinogen, and α1-antitrypsin. HNF1 is expressed in the liver, digestive tract, pancreas, and kidney. Mice lacking HNF1 exhibit hepatic, pancreatic, and renal dysfunctions. HNF1-deficient mice fail to express the hepatic phenylalanine hydroxylase gene, giving rise to hyperphenylalaninemia. Renal proximal tubular reabsorption of glucose, phosphate, arginine, and other metabolites is affected, producing severe renal glucosuria, phosphaturia, and amino aciduria. Homozygous mutant mice also exhibit a dramatic insulin secretion defect. This dysfunction resembles that exhibited by patients with maturity-onset diabetes mellitus of the young type 3, who carry mutations in the human HNF1 gene in the heterozygous state. These data show that HNF1 is a major regulator of glucose homeostasis, regulating the expression of genes that are expressed in the liver, kidney, and pancreas.
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Bártů, Michaela, P. Dundr, K. Němejcová, I. Tichá, H. Hojný, and N. Hájková. "The Role of HNF1B in Tumorigenesis of Solid Tumours: a Review of Current Knowledge." Folia Biologica 64, no. 3 (2018): 71–83. http://dx.doi.org/10.14712/fb2018064030071.
Анотація:
Hepatocyte nuclear factor 1-β is a transcription factor which plays a crucial role during ontogenesis in the differentiation of visceral endoderm from primitive endoderm, and is especially important for the normal development of the kidney, urogenital tract, gastrointestinal tract, liver, and pancreas. Despite the growing knowledge about the potential involvement of hepatocyte nuclear factor 1-β in the process of carcinogenesis, the exact underlying mechanism that would explain its rather varied effects in different tumours has not been sufficiently investigated. Most of the data regarding the significance of hepatocyte nuclear factor 1-β arise from genome- wide association studies and is concerned with the influence of single-nucleotide polymorphisms of hepatocyte nuclear factor 1-β on either the increased or decreased susceptibility to certain types of cancer. However, the influence of both the germinal and somatic mutations of this gene on the process of carcinogenesis is still poorly understood. According to current data, in some tumours hepatocyte nuclear factor 1-β acts as a protooncogene, while in others as a tumour suppressor gene, although the reasons for this are not clear. The exact incidence of hepatocyte nuclear factor 1-β mutations and the spectrum of tumours in which they may play a role in the process of carcinogenesis remain unknown. From the practical point of view, immunohistochemical expression of hepatocyte nuclear factor 1-β can be used in differential diagnostics of certain tumours, especially clear cell carcinoma. In our article we review the current knowledge regarding the significance of hepatocyte nuclear factor 1-β in carcinogenesis.
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MCNAIR, Alan, Silvia CEREGHINI, Heike BRAND, Terry SMITH, Christelle BREILLAT, and Frank GANNON. "Synergistic activation of the Atlantic salmon hepatocyte nuclear factor (HNF) 1 promoter by the orphan nuclear receptors HNF4 and chicken ovalbumin upstream promoter transcription factor I (COUP-TFI)." Biochemical Journal 352, no. 2 (November 24, 2000): 557–64. http://dx.doi.org/10.1042/bj3520557.
Анотація:
Hepatocyte nuclear factor 1 (HNF1) is a liver-enriched transcription factor that plays an important role in transcriptional networks involved in liver function. The promoters of mammalian HNF1 genes contains a single binding site for another liver-enriched transcription factor, the nuclear hormone receptor HNF4. A transcriptional hierarchy involving HNF4-mediated activation of the HNF1 promoter has been proposed to be of crucial importance in maintaining the differentiated hepatocyte phenotype. Here we present evidence that the Atlantic salmon HNF1 promoter contains three nuclear-hormone-receptor-binding sequences. Gel-shift assays showed that these motifs are recognized with different affinities by HNF4 and the orphan nuclear receptors chicken ovalbumin upstream promoter transcription factors COUP-TFI and COUP-TFII. In hepatoma cells, the site showing highest affinity for HNF4 appears to be crucial for promoter activity. Transfection experiments in non-hepatic cells indicated that the salmon HNF1 promoter was activated by both HNF4 and COUP-TFs. We also identified a promoter fragment encompassing the two more distal nuclear-hormone-binding sites that was activated by HNF4, unaffected by COUP-TF and showed a strong synergistic activation by HNF4/COUP-TF. Results are presented detailing these interactions in relation to the salmon HNF1 promoter architecture.
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Sucajtys-Szulc, Elzbieta, Alicja Debska-Slizien, Boleslaw Rutkowski, Marek Szolkiewicz, Julian Swierczynski та Ryszard Tomasz Smolenski. "Hepatocyte Nuclear Factor 1α Proinflammatory Effect Linked to the Overexpression of Liver Nuclear Factor–κB in Experimental Model of Chronic Kidney Disease". International Journal of Molecular Sciences 23, № 16 (10 серпня 2022): 8883. http://dx.doi.org/10.3390/ijms23168883.
Анотація:
Chronic kidney disease (CKD) is associated with low-grade inflammation that activates nuclear factor–κB (NF–κB), which upregulates the expression of numerous NF–κB responsive genes, including the genes encoding IL-6, ICAM-1, VCAM-1, and MCP-1. Herein, we found the coordinated overexpression of genes encoding RelA/p65 (a subunit of NF–κB) and HNF1α in the livers of chronic renal failure (CRF) rats—an experimental model of CKD. The coordinated overexpression of RelA/p65 and HNF1α was associated with a significant increase in IL-6, ICAM-1, VCAM-1, and MCP-1 gene expressions. A positive correlation between liver RelA/p65 mRNA levels and a serum concentration of creatinine and BUN suggest that RelA/p65 gene transcription is tightly related to the progression of renal failure. The knockdown of HNF1α in the HepG2 cell line by siRNA led to a decrease in Rel A/p65 mRNA levels. This was associated with a decrease in IL-6, ICAM-1, VCAM-1, and MCP-1 gene expressions. The simultaneous repression of HNF-1α and RelA/p65 by clofibrate is tightly associated with the downregulation of IL-6, ICAM-1, VCAM-1, and MCP-1 gene expression. In conclusion, our findings suggest that NF–κB could be a downstream component of the HNF1α-initiated signaling pathway in the livers of CRF rats.
27
Chaya, D., C. Fougère-Deschatrette, and M. C. Weiss. "Liver-enriched transcription factors uncoupled from expression of hepatic functions in hepatoma cell lines." Molecular and Cellular Biology 17, no. 11 (November 1997): 6311–20. http://dx.doi.org/10.1128/mcb.17.11.6311.
Анотація:
Among the liver-enriched transcription factors identified to date, only expression of hepatocyte nuclear factor 4 (HNF4) and hepatocyte nuclear factor 1 (HNF1) is in strict correlation with hepatic differentiation in cultured rat hepatoma cells. Indeed, differentiated hepatoma cells that stably express an extensive set of adult hepatic functions express liver-enriched transcription factors, while dedifferentiated cells that have lost expression of all these hepatic functions no longer express HNF4 and HNF1. We describe a new heritable phenotype, designated as uncoupled, in which there is a spontaneous dissociation between the expression of these transcription factors and that of the hepatic functions. Cells presenting this phenotype, isolated from differentiated hepatoma cells, cease to accumulate all transcripts coding for hepatic functions but nevertheless maintain expression of HNF4 and HNF1. Transitory transfection experiments indicate that these two factors present in these cells have transcriptional activity similar to that of differentiated hepatoma cells. Characterization of the appropriate intertypic cell hybrids demonstrates that this new phenotype is recessive to the dedifferentiated state and fails to be complemented by differentiated cells. These results indicate the existence of mechanisms that inhibit transcription of genes coding for hepatocyte functions in spite of the presence of functional HNF4 and HNF1. Cells of the uncoupled phenotype present certain properties of oval cells described for pathological states of the liver.
28
Vaulont, S., N. Puzenat, A. Kahn, and M. Raymondjean. "Analysis by cell-free transcription of the liver-specific pyruvate kinase gene promoter." Molecular and Cellular Biology 9, no. 10 (October 1989): 4409–15. http://dx.doi.org/10.1128/mcb.9.10.4409-4415.1989.
Анотація:
A DNA fragment spanning nucleotides -183 to -4 with respect to the cap site of the rat L-type pyruvate kinase (L-PK) gene contains at least four binding sites for putative transcriptional factors: hepatocyte nuclear factor 1 (HNF1), liver factor A1 (LF-A1), nuclear factor 1 (NF1), and major late transcription factor (MLTF). This fragment was used to direct transcription of a reporter sequence (a G-free cassette) in cell extracts. This L-PK promoter was active in liver nuclear extracts, but not in extracts from nonhepatic tissues. A reduction of 50% of the activity was obtained with a deleted L-PK promoter containing only the HNF1-binding site. In contrast, deletion of the HNF1-binding site inactivated the promoter by more than 90%. These results were confirmed by titration experiments with synthetic oligonucleotides. Titration of HNF1 resulted in an 85% decrease of transcriptional activity, while titration of LF-A1 resulted in only a 40% decrease. The influence of NF1 and MLTF seemed to be marginal in this system. The proximal 5'-flanking sequence of the L-PK gene therefore appears to function in vitro as an efficient liver-specific promoter which requires the binding of the liver factor HNF1 and which is also stimulated by the binding of another liver-specific factor, LF-A1.
29
Vaulont, S., N. Puzenat, A. Kahn, and M. Raymondjean. "Analysis by cell-free transcription of the liver-specific pyruvate kinase gene promoter." Molecular and Cellular Biology 9, no. 10 (October 1989): 4409–15. http://dx.doi.org/10.1128/mcb.9.10.4409.
Анотація:
A DNA fragment spanning nucleotides -183 to -4 with respect to the cap site of the rat L-type pyruvate kinase (L-PK) gene contains at least four binding sites for putative transcriptional factors: hepatocyte nuclear factor 1 (HNF1), liver factor A1 (LF-A1), nuclear factor 1 (NF1), and major late transcription factor (MLTF). This fragment was used to direct transcription of a reporter sequence (a G-free cassette) in cell extracts. This L-PK promoter was active in liver nuclear extracts, but not in extracts from nonhepatic tissues. A reduction of 50% of the activity was obtained with a deleted L-PK promoter containing only the HNF1-binding site. In contrast, deletion of the HNF1-binding site inactivated the promoter by more than 90%. These results were confirmed by titration experiments with synthetic oligonucleotides. Titration of HNF1 resulted in an 85% decrease of transcriptional activity, while titration of LF-A1 resulted in only a 40% decrease. The influence of NF1 and MLTF seemed to be marginal in this system. The proximal 5'-flanking sequence of the L-PK gene therefore appears to function in vitro as an efficient liver-specific promoter which requires the binding of the liver factor HNF1 and which is also stimulated by the binding of another liver-specific factor, LF-A1.
30
Hayhurst, Graham P., Ying-Hue Lee, Gilles Lambert, Jerrold M. Ward та Frank J. Gonzalez. "Hepatocyte Nuclear Factor 4α (Nuclear Receptor 2A1) Is Essential for Maintenance of Hepatic Gene Expression and Lipid Homeostasis". Molecular and Cellular Biology 21, № 4 (15 лютого 2001): 1393–403. http://dx.doi.org/10.1128/mcb.21.4.1393-1403.2001.
Анотація:
ABSTRACT The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1α [HNF1α], -1β, -3α, -3β, -3γ, -4α, and -6 and members of the c/ebp family). Of these, only HNF4α (nuclear receptor 2A1) and HNF1α appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1α-null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4α-null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4α is indispensable for hepatocyte differentiation. However, the function of HNF4α in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4α in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4α expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4α is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.
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Prestin, Katharina, Janine Hussner, Celio Ferreira, Isabell Seibert, Vivien Breitung, Uwe Zimmermann та Henriette E. Meyer zu Schwabedissen. "Regulation of PDZ domain-containing 1 (PDZK1) expression by hepatocyte nuclear factor-1α (HNF1α) in human kidney". American Journal of Physiology-Renal Physiology 313, № 4 (1 жовтня 2017): F973—F983. http://dx.doi.org/10.1152/ajprenal.00650.2016.
Анотація:
In the renal proximal tubule the secretion and reabsorption of glomerularly filtrated compounds is realized by a functional network of uptake and efflux transporters. The activity and localization of several transporters expressed at the apical tubular membrane are regulated by the membrane-associated protein PDZ domain-containing 1 (PDZK1). We aimed to characterize the transcriptional regulation of this modulator of renal transport. Coexpression analyses of PDZK1 and putative regulators were performed using human kidney samples. Protein and mRNA expression of PDZK1 in renal proximal tubule epithelial cells after adenoviral transfer and siRNA knockdown of transcription factor hepatocyte nuclear factor-1α (HNF1α) was assessed by quantitative real-time PCR and Western blot analysis. Transactivation of the PDZK1 promoter was quantified in cell-based reporter gene assays. Subsequently, the binding of HNF1α to the PDZK1 promoter was verified by in silico analyses and chromatin immunoprecipitation assay. HNF1α positively regulated the promoter activity of PDZK1. Adenoviral overexpression of HNF1α in renal proximal tubule epithelial cells (RPTEC) increased PDZK1 mRNA and protein expression, whereas siRNA knockdown of HNF1α resulted in decreased expression of PDZK1. Our results show that HNF1α, which has previously been described as a modulator of several transporters of the renal transportosome, is also a key determinant of PDZK1 transcription.
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Montgomery, Emma K., and John A. Sayer. "FP054PHENOTYPIC ANALYSIS OF A COHORT OF PATIENTS WITH HEPATOCYTE NUCLEAR FACTOR 1 BETA (HNF1b) MUTATIONS." Nephrology Dialysis Transplantation 30, suppl_3 (May 2015): iii82—iii83. http://dx.doi.org/10.1093/ndt/gfv167.10.
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Veerareddy, Sudiksha, Saigopala Reddy, Mauricio Barreto, Niharika Vedherey, and Vani V. Gopalareddy. "Increased Liver Enzymes: An Under-Recognized Finding in Maturity-Onset Diabetes of the Young Type 5 (MODY 5)." ACG Case Reports Journal 10, no. 10 (October 2023): e01150. http://dx.doi.org/10.14309/crj.0000000000001150.
Анотація:
ABSTRACT Maturity-onset diabetes of the young type 5 (MODY 5) is characterized by a single gene mutation in the HNF1B gene. This frequently leads to insulin resistance and presents as young-onset diabetes. Other manifestations can occur in organs expressing hepatocyte nuclear factor-1 beta. This case report highlights family members with MODY 5 presenting with increased liver enzymes with no etiology. The siblings and their mother had a point mutation p.Arg235Trp in HNF1B gene located at 17q12. This variant is associated with autosomal dominant MODY 5 with renal cysts also known as renal cysts and diabetes syndrome.
34
MOUCHEL, Nathalie, Sytse A. HENSTRA, Victoria A. McCARTHY, Sarah H. WILLIAMS, Marios PHYLACTIDES, and Ann HARRIS. "HNF1alpha is involved in tissue-specific regulation of CFTR gene expression." Biochemical Journal 378, no. 3 (March 15, 2004): 909–18. http://dx.doi.org/10.1042/bj20031157.
Анотація:
The CFTR (cystic fibrosis transmembrane conductance regulator) gene shows a complex pattern of expression with tissue-specific and temporal regulation. However, the genetic elements and transcription factors that control CFTR expression are largely unidentified. The CFTR promoter does not confer tissue specificity on gene expression, suggesting that there are regulatory elements outside the upstream region. Analysis of potential regulatory elements defined as DNase 1-hypersensitive sites within introns of the gene revealed multiple predicted binding sites for the HNF1α (hepatocyte nuclear factor 1α) transcription factor. HNF1α, which is expressed in many of the same epithelial cell types as CFTR and shows similar differentiation-dependent changes in gene expression, bound to these sites in vitro. Overexpression of heterologous HNF1α augmented CFTR transcription in vivo. In contrast, antisense inhibition of HNF1α transcription decreased the CFTR mRNA levels. Hnf1α knockout mice showed lower levels of CFTR mRNA in their small intestine in comparison with wild-type mice. This is the first report of a transcription factor, which confers tissue specificity on the expression of this important disease-associated gene.
35
van der Made, Cas I., Ewout J. Hoorn, Renaud de la Faille, Huseyin Karaaslan, Nine V. A. M. Knoers, Joost G. J. Hoenderop, Rosa Vargas Poussou, and Jeroen H. F. de Baaij. "Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review." American Journal of Nephrology 42, no. 1 (2015): 85–90. http://dx.doi.org/10.1159/000439286.
Анотація:
Background: Autosomal dominant tubulointerstitial kidney disease subtype HNF1B (ADTKD-HNF1B) is caused by a mutation in hepatocyte nuclear factor 1 homeobox beta (HNF1B). Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural kidney defects or diabetes. Cases: The current case series describes 3 patients in whom hypomagnesemia proved to be the first clinical manifestation of ADTKD-HNF1B. All patients presented with hypomagnesemia with a high fractional excretion of Mg2+ and hypocalciuria. Exome sequencing performed for analysis of known and candidate hypomagnesaemia genes and subsequent multiplex ligation-dependent probe amplification analysis revealed a large deletion at the chromosome 17q12. Follow-up analysis showed increased blood glucose concentrations in all 3 patients and high hemoglobin A1c levels in 2 out of 3 patients, indicating diabetes mellitus. Although all patients suffered from mild renal insufficiency, only 1 of the 3 patients was shown to have renal cysts on CT. Conclusion: The prevalence of HNF1B mutations and the relative contribution of hypomagnesemia to its symptoms are underestimated. Therefore, patients with primary renal magnesium wasting should be tested for HNF1B mutations to ensure early detection and optimal management of ADTKD-HNF1B.
36
Olsen, J., I. Classen-Linke, H. Sjöström та O. Norén. "Pseudopregnancy induces the expression of hepatocyte nuclear factor-1β and its target gene aminopeptidase N in rabbit endometrium via the epithelial promoter". Biochemical Journal 312, № 1 (15 листопада 1995): 31–37. http://dx.doi.org/10.1042/bj3120031.
Анотація:
The rabbit endometrium is an excellent model system allowing experimental manipulation of aminopeptidase N (APN) mRNA expression in vivo. By RNase mapping and sequencing of cloned PCR-amplified primer-extended RNA, it was demonstrated that endometrial APN expression is directed by the epithelial APN promoter and is increased in human-choriogonadotropin-induced pseudopregnancy. Cloning and sequencing of the rabbit APN epithelial promoter revealed conservation of the upstream footprint (UF), hepatocyte nuclear factor-1 (HNF1) and Sp1 elements known to be present in the pig and human promoters as well. The pseudopregnancy-induced APN expression was found to be accompanied by a parallel increase in the level of the transcription factor HNF1 beta, whereas a much smaller increase in Sp1 and UF-binding proteins was observed. This indicates that HNF1 beta acts as a switch triggering the pregnancy-induced APN expression. The sequence of the UF element suggests members of the nuclear hormone-receptor superfamily as possible UF-binding proteins, and competition experiments suggest that the chicken ovalbumin upstream promoter transcription factor functions as such in the rabbit endometrium.
37
Park, Seung Shin, and Soo Heon Kwak. "Maturity-Onset Diabetes of the Young (MODY)." Journal of Korean Diabetes 23, no. 3 (September 30, 2022): 157–64. http://dx.doi.org/10.4093/jkd.2022.23.3.157.
Анотація:
Precision medicine, which optimizes diagnosis and treatment of diseases according to individualized characteristics, is becoming a reality in the field of diabetes, especially for monogenic diabetes. Maturityonset diabetes of the young (MODY) is a type of monogenic diabetes characterized by early onset, relative non-obesity, non-insulin dependence, and autosomal dominant inheritance. With the trend toward precision medicine and improvement in genetic testing, there have been advances in the classification, diagnosis, and treatment of MODY. MODY accounts for about 1% of diabetes in Korea, with GCK (glucokinase)-MODY, HNF1α (hepatocyte nuclear factor-1 alpha)-MODY, and HNF4α (hepatocyte nuclear factor-4 alpha)-MODY being most common. In the diagnosis of MODY, applying guidelines for interpretation of variant pathogenicity is important. For the treatment of MODY, individualized treatment strategies according to the causative gene of MODY should be applied when available. Still, the majority of MODY is misdiagnosed and more genetic testing is required in Korea. We review updates regarding the classification, diagnosis, and treatment of MODY.
38
Zhao, Juanjuan, Katherine Lupino, Benjamin J. Wilkins, Chengxiang Qiu, Jian Liu, Yasuhiro Omura, Amanda L. Allred та ін. "Genomic integration of ERRγ-HNF1β regulates renal bioenergetics and prevents chronic kidney disease". Proceedings of the National Academy of Sciences 115, № 21 (7 травня 2018): E4910—E4919. http://dx.doi.org/10.1073/pnas.1804965115.
Анотація:
Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1β) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1β. Deletion of ERRγ in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1β loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1β-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.
39
Spiro, Andrew J., Katherine N. Vu, and Alicia Lynn Warnock. "An Atypical HNF4A Mutation Which Does Not Conform to the Classic Presentation of HNF4A-MODY." Case Reports in Endocrinology 2018 (May 28, 2018): 1–4. http://dx.doi.org/10.1155/2018/1560472.
Анотація:
Objective. To present the case of an atypical Hepatocyte Nuclear Factor 4 Alpha (HNF4A) mutation that is not consistent with the classically published presentation of HNF4A-Mature Onset Diabetes of the Young (MODY). Methods. Clinical presentation and literature review. Results. A 43-year-old nonobese man was referred to the endocrinology clinic for evaluation of elevated fasting blood glucose (FBG) measurements. Laboratory review revealed prediabetes and hypertriglyceridemia for the previous decade. Testing of autoantibodies for type 1 diabetes was negative. Genetic testing showed an autosomal dominant, heterozygous missense mutation (c.991C>T; p.Arg331Cys) in the HNF4A gene, which is correlated with HNF4A-MODY. Phenotypically, patients with an HNF4A-MODY tend to have early-onset diabetes, microvascular complications, low triglyceride levels, increased birth weight, fetal macrosomia, and less commonly neonatal hyperinsulinemic hypoglycemia. The patient did not demonstrate any of these features but instead presented with late-onset diabetes, an elevated triglyceride level, and a normal birth weight. Conclusion. Our patient likely represents an atypical variant of HNF4A-MODY with a milder clinical presentation. Patients with atypical, less-severe presentations of HNF4A-MODY may be largely undiagnosed or misdiagnosed, but identification is important due to implications for treatment, pregnancy, and screening of family members.
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Sahu, Ravi P., Ajay Aggarwal, Ghazala Zaidi, Ajay Shah, Kirti Modi, Srikanth Kongara, Suraksha Aggarwal та ін. "Etiology of Early-Onset Type 2 Diabetes in Indians: Islet Autoimmunity and Mutations in Hepatocyte Nuclear Factor 1α and Mitochondrial Gene". Journal of Clinical Endocrinology & Metabolism 92, № 7 (1 липня 2007): 2462–67. http://dx.doi.org/10.1210/jc.2006-2467.
Анотація:
Abstract Context: Indians are at high risk of developing type 2 diabetes mellitus (T2DM) at an early age, despite their lower body mass index. Studies on the etiology of patients presenting as early-onset T2DM in this racial group are not available. Objective: The objective was to delineate the clinical features in young Indian patients with T2DM and to determine the role of mutations in the hepatocyte nuclear factor 1α (HNF1α) gene [MODY3 (maturity-onset diabetes of the young, type 3)], mitochondrial A3243G mutation, and islet autoimmunity in its etiology. Design: This was an observational cohort study. Setting: The setting was an outpatient diabetes clinic in a teaching hospital. Patients: Ninety-six consecutive young patients with T2DM (onset, ≤30 yr) were included in the study. Interventions: Glutamic acid decarboxylase and insulinoma antigen 2 antibodies, mitochondrial A3243G mutation, and the common HNF1α mutation P291fsinsC were measured in all patients. The entire HNF1α gene was studied for mutations in 32 subjects with onset less than 25 yr or with normal weight. The common HNF1α A98V polymorphism was studied in 91 patients. Results: The patients were clinically heterogeneous, with 42% having a normal body mass index. Glutamic acid decarboxylase antibodies were present in three (3%) subjects and mitochondrial A3243G mutation in one (1%) subject. The P291fsinsC mutation was not detected in any patient. A MODY3 mutation (R200W) was detected in one patient (3%). In this family, diabetes cosegregated with the R200W mutation in the proband and his youngest brother but not in three paternal uncles. The Val 98 allele was associated with T2DM (allele frequency, 0.14 vs. 0.03 in controls; odds ratio, 5.2; P < 0.001). Conclusions: Despite a significant proportion of young Indian patients with T2DM having normal weight, islet autoimmunity, A3243G mitochondrial, and HNF1α gene mutations were infrequent.
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Ugonabo, Onyinye, Turki Mohamed, Murad Kheetan, and Ahmed Sherif. "Failure to Thrive in a Middle-Aged Female: A Case of Congenital Incomplete Pancreas From a Rare Genetic Defect." Journal of Investigative Medicine High Impact Case Reports 11 (January 2023): 232470962311657. http://dx.doi.org/10.1177/23247096231165742.
Анотація:
Hepatocyte nuclear factor-1 beta (HNF1B) gene is predominantly expressed in the liver, kidney, lung, genitourinary tract, and pancreas. It is an important transcription factor that regulates pancreas development. Mutation or absence of this gene is rare and can cause incomplete pancreatic development known as the agenesis of the dorsal pancreas. This rare genetic abnormality is associated with other disorders like maturity-onset diabetes of the young, abnormal liver function tests, genitourinary tract malformation, pancreatitis, and renal cysts. Diagnosing this genetic abnormality is difficult, especially in patients presenting with symptoms specific to only one system. Management is based on disease manifestation and involves a multidisciplinary approach. Our case describes a 51-year-old female with poorly controlled diabetes mellitus and Mullerian duct anomalies who presented with abdominal pain, fatigue, dizziness, and electrolyte derangement. Contrast-enhanced computed tomography (CECT) of the abdomen showed a multicystic kidney and a pancreatic head with a missing body and tail. Further workup revealed an HNF1B mutation.
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Pastoret, Anna, Ricard Marcos, Adriana Sampayo-Reyes, Odila Saucedo-Cardenas, Gerardo H. Lozano-Garza та Alba Hernandez. "Inhibition of hepatocyte nuclear factor 1 and 4 alpha (HNF1α and HNF4α) as a mechanism of arsenic carcinogenesis". Archives of Toxicology 87, № 6 (5 жовтня 2012): 1001–12. http://dx.doi.org/10.1007/s00204-012-0948-6.
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Welters, Hannah J., Sabine Senkel, Ludger Klein-Hitpass, Silke Erdmann, Heike Thomas, Lorna W. Harries, Ewan R. Pearson та ін. "Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic β-cells". Journal of Endocrinology 190, № 1 (липень 2006): 171–81. http://dx.doi.org/10.1677/joe.1.06768.
Анотація:
Mutations in the gene encoding hepatocyte nuclear factor (HNF)1β result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing β-cell mass. The functional role of HNF1β in normal β-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1β, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic β-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1β was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1β also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent β-cells are sensitive to increased expression of WT HNF1β and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.
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Fujiwara, Kei, Yasuhito Tanaka, Emma Paulon, Etsuro Orito, Masaya Sugiyama, Kiyoaki Ito, Ryuzo Ueda, Masashi Mizokami, and Nikolai V. Naoumov. "Novel Type of Hepatitis B Virus Mutation: Replacement Mutation Involving a Hepatocyte Nuclear Factor 1 Binding Site Tandem Repeat in Chronic Hepatitis B Virus Genotype E." Journal of Virology 79, no. 22 (November 15, 2005): 14404–10. http://dx.doi.org/10.1128/jvi.79.22.14404-14410.2005.
Анотація:
ABSTRACT The genetic diversity of hepatitis B virus (HBV) strains has evolved through mutations such as point mutations, deletions or insertions, and recombination. We identified and characterized a novel type of mutation which is a complex of external insertion, deletion, and internal duplication in sequences from one of six patients with chronic hepatitis B virus genotype E (HBV/E). We provisionally named this mutation a “replacement mutation”; the core promoter upstream regulatory sequence/basic core promoter was replaced with a part of the S1 promoter covering the hepatocyte nuclear factor 1 (HNF1) binding site, followed by a tandem repeat of the HNF1 site. A longitudinal analysis of the HBV population over 6 years showed the clonal change from wild-type HBV/E to replacement-mutant type, resulting in a lower hepatitis B (HB) e antigen titer, a high HBV DNA level in serum, and progression of liver fibrosis. In an in vitro study using a replication model, the replacement-mutant HBV showed higher replication levels than the wild-type HBV/E replicon, probably mediated by altered transcription factor binding. Additionally, this HNF1 site replacement mutation was associated with excessive HB nucleocapsid protein expression in hepatocytes, in both in vivo and in vitro studies. This novel mutation may be specific to HBV genotype E, and its prevalence requires further investigation.
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VOSS, Susan H., Richard WHALEN, and Thomas D. BOYER. "Mechanism of negative regulation of rat glutathione S-transferase A2 by the cytokine interleukin 6." Biochemical Journal 365, no. 1 (July 1, 2002): 229–37. http://dx.doi.org/10.1042/bj20011514.
Анотація:
A decrease in concentration of some liver proteins, including the detoxification enzyme glutathione S-transferase A2 (rGSTA2), occurs during the acute-phase response. Interleukin 6 (IL-6) with dexamethasone (DEX) decreases transcription of rGSTA2 in rat hepatocytes. The promoter region that mediates suppression of rGSTA2 was localized to 150bp. These 150bp were divided and used for electrophoretic mobility-shift assays. Induction of a protein that specifically bound to an oligonucleotide from this region required new protein synthesis and IL-6 with DEX in the culture media. The protein bound to part of the hepatocyte nuclear factor 1 (HNF1) site but was different from and did not displace HNF1. A core sequence, TGATT, was required for binding. The protein also bound to an HNF1 site in the albumin promoter. We hypothesize that IL-6 along with DEX induced a novel protein that decreased transcription of rGSTA2 and possibly albumin by interfering with the transactivating function of HNF1. The protein may be an important negative regulator of transcription during the acute-phase response.
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Eeckhoute, Jérôme, Pierre Formstecher та Bernard Laine. "Maturity-Onset Diabetes of the Young Type 1 (MODY1)-Associated Mutations R154X and E276Q in Hepatocyte Nuclear Factor 4α (HNF4α) Gene Impair Recruitment of p300, a Key Transcriptional Coactivator". Molecular Endocrinology 15, № 7 (1 липня 2001): 1200–1210. http://dx.doi.org/10.1210/mend.15.7.0670.
Анотація:
Abstract Hepatocyte nuclear factor 4α (HNF4α) is a nuclear receptor involved in glucose homeostasis and is required for normal β-cell function. Mutations in the HNF4α gene are associated with maturity-onset diabetes of the young type 1. E276Q and R154X mutations were previously shown to impair intrinsic transcriptional activity (without exogenously supplied coactivators) of HNF4α. Given that transcriptional partners of HNF4α modulate its intrinsic transcriptional activity and play crucial roles in HNF4α function, we investigated the effects of these mutations on potentiation of HNF4α activity by p300, a key coactivator for HNF4α. We show here that loss of HNF4α function by both mutations is increased through impaired physical interaction and functional cooperation between HNF4α and p300. Impairment of p300-mediated potentiation of HNF4α transcriptional activity is of particular importance for the E276Q mutant since its intrinsic transcriptional activity is moderately affected. Together with previous results obtained with chicken ovalbumin upstream promoter-transcription factor II, our results highlight that impairment of recruitment of transcriptional partners represents an important mechanism leading to abnormal HNF4α function resulting from the MODY1 E276Q mutation. The impaired potentiations of HNF4α activity were observed on the promoter of HNF1α, a transcription factor involved in a transcriptional network and required for β-cell function. Given its involvement in a regulatory signaling cascade, loss of HNF4α function may cause reduced β-cell function secondary to defective HNF1α expression. Our results also shed light on a better structure-function relationship of HNF4α and on p300 sequences involved in the interaction with HNF4α.
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Santiago, Jose A., and Judith A. Potashkin. "Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease." Proceedings of the National Academy of Sciences 112, no. 7 (February 2, 2015): 2257–62. http://dx.doi.org/10.1073/pnas.1423573112.
Анотація:
Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson’s disease (PD), the second most prevalent neurodegenerative disease among the elderly. Network-based metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were up- and down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson’s Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y follow-up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.
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ARSLAN, Remzi. "Diagnostic importance of hepatocyte nuclear factor 1 beta (HNF1β) in testicular tumors and its sensitivity for the detection of yolk sac tumors: an immunohistochemical analysis". European Research Journal 8, № 4 (4 липня 2022): 497–505. http://dx.doi.org/10.18621/eurj.1112501.
Анотація:
Objectives: Testicular tumors are common solid malignancies in young fertile men, and most are germ cell tumors. In general, they originate from a single germ cell and transform into different tumor types or present with the coexistence of different morphological patterns. Due to the heterogeneity of these tumors, immunohistochemical markers are frequently used in their differential diagnosis. In recent years, some studies have indicated hepatocyte nuclear factor 1 beta (HNF1β) can be used in the differential diagnosis of testicular tumors, especially yolk sac tumors (YSTs). In this study, we aimed to investigate the general expression status of HNF1β in all testicular tumors and determine its importance in YST detection. Methods: A total of 144 testicular tumors treated with orchiectomy between 2011 and 2020 were included in our study. The pathological diagnosis reports of these cases were retrospectively reviewed and their general prognostic features were determined. HNF1β immunohistochemical staining was applied to the characteristic paraffin blocks representing the lesions. Staining was evaluated in terms of severity and prevalence. Results: Most cases (38.2%) were seminomas, followed by mixed germ cell tumors (34.0%, 49/144), embryonic carcinomas (7.6%), pure YSTs (4.9%), and others (Leydig cell tumors, mesenchymal tumors, lymphomas, etc.). No HNF1β immunostaining was observed in any of the seminomatous lesions. A high level of staining was present in almost all the pure YSTs and tumor areas with the YST component. HNF1β had a specificity of 95.1% and sensitivity of 87.1% in the detection of YSTs. Conclusions: HNF1β has high specificity and sensitivity in detecting YSTs among testicular tumors, and therefore we consider that it can be routinely used to detect the presence of YSTs, especially in patients with mixed germ cell tumors.
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Kim, Sung-Jun, So-Jung Kim, Jeongeun Hyun, Hae-Won Kim, and Jun-Hyeog Jang. "Regeneration of Non-Alcoholic Fatty Liver Cells Using Chimeric FGF21/HGFR: A Novel Therapeutic Approach." International Journal of Molecular Sciences 25, no. 6 (March 7, 2024): 3092. http://dx.doi.org/10.3390/ijms25063092.
Анотація:
Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant liver ailment attributed to factors like obesity and diabetes. While ongoing research explores treatments for NAFLD, further investigation is imperative to address this escalating health concern. NAFLD manifests as hepatic steatosis, precipitating insulin resistance and metabolic syndrome. This study aims to validate the regenerative potential of chimeric fibroblast growth factor 21 (FGF21) and Hepatocyte Growth Factor Receptor (HGFR) in NAFLD-afflicted liver cells. AML12, a murine hepatocyte cell line, was utilized to gauge the regenerative effects of chimeric FGF21/HGFR expression. Polysaccharide accumulation was affirmed through Periodic acid–Schiff (PAS) staining, while LDL uptake was microscopically observed with labeled LDL. The expression of FGF21/HGFR and NAFLD markers was analyzed by mRNA analysis with RT-PCR, which showed a decreased expression in acetyl-CoA carboxylase 1 (ACC1) and sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) with increased expression of hepatocellular growth factor (HGF), hepatocellular nuclear factor 4 alpha (HNF4A), and albumin (ALB). These findings affirm the hepato-regenerative properties of chimeric FGF21/HGFR within AML12 cells, opening novel avenues for therapeutic exploration in NAFLD.
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Griffing, Emily, and Sarah J. L. Tsai. "LBODP032 Case Report Of A 13 Years Old Female With A Novel Pathogenic Variant In The Hnf1b Gene." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A264. http://dx.doi.org/10.1210/jendso/bvac150.542.
Анотація:
Abstract Background MODY5 results from mutations in the gene encoding hepatocyte nuclear factor 1 homeobox B (HNF1B), a transcription factor critical in development of the pancreas, liver, intestines, and the urogenital tract (1). We report the case of a pediatric patient with a novel frameshift variant (p. Phe309SerfsTer18) in the HNF1B gene accounting for the co-occurrence of diabetes mellitus and structural renal abnormalities. Clinical case: A 13-years-old female with chronic kidney disease stage 3 (eGFR = 48 ml/min/1.73m2) secondary to congenital dysplastic-appearing left kidney and surgical removal of a cystic dysplastic right kidney was referred to our diabetes clinic for hyperglycemia. She reported long-standing polyuria and polydipsia previously attributed to her kidney disease. She required laparoscopic right nephrectomy at age 5 years due to increasing cyst size. Her left kidney also has small renal parenchymal cysts which have been monitored over time. There is no known family history of kidney disease, and grandparents have a history of diabetes. Laboratory investigation revealed a random blood glucose of 478 mg/dL and a hemoglobin A1c of 12.2%. She was not in diabetic ketoacidosis. She had a detectable insulin level of 5.1 mcIU/mL and C-peptide was 3.4 ng/mL. She was initially presumed to have Type 1 diabetes based on a relatively low insulin level and started on basal-bolus insulin (up to 0.59 units/kg of weight/day). Glycosylated hemoglobin was 8.7% one month after diagnosis. Glutamic acid decarboxylase, zinc transporter, islet cell, and insulin autoantibodies were not detected, however, and she was then suspected to have either Type 2 diabetes or MODY. Approximately one year later, she was taken off insulin due to hypoglycemia and managed only with metformin 500 mg twice daily. Next-generation sequencing revealed a de novo pathogenic variant in HNF1B causing a frameshift deletion (p. Phe309SerfsTer18). Genetic testing of parents was negative. Once her diagnosis of MODY5 was made, she was started on glipizide 2.5 mg once daily which has been titrated up to a dose of 5 mg with some success. However, she has since been re-started on insulin (up to 0.2 units/kg/day) due to hyperglycemia keeping in line with the MODY5 phenotype likely causing destruction of beta cells over time (1). Conclusion We report a case of MODY5 with a novel frameshift mutation (p. Phe309SerfsTer18) in the HNF1B gene. This case highlights the importance of screening for HNF-1B mutations in those patients with structural renal abnormalities and hyperglycemia, as diagnosis can guide management decisions and provide prognostic information. Reference Bellanné-Chantelot C, Chauveau D, Gautier JF, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140(7): 510-517. doi: 10.7326/0003-4819-140-7-200404060-0000 Presentation: No date and time listed