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Sian Ellard - One of the best experts on this subject based on the ideXlab platform.
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mutations in the genes encoding the transcription Factors Hepatocyte Nuclear Factor 1 alpha and 4 alpha in maturity onset diabetes of the young and hyperinsulinemic hypoglycemia
Human Mutation, 2013Co-Authors: Kevin Colclough, Christine Bellannechantelot, Cecile Saintmartin, Sarah E Flanagan, Sian EllardAbstract:Maturity-onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young-onset (typically <25 years), noninsulin-dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding Hepatocyte Nuclear Factor-1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding Hepatocyte Nuclear Factor-4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ∼50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost-effective gene analysis for all patients with young onset diabetes.
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urinary c peptide creatinine ratio is a practical outpatient tool for identifying Hepatocyte Nuclear Factor 1 α Hepatocyte Nuclear Factor 4 α maturity onset diabetes of the young from long duration type 1 diabetes
Diabetes Care, 2011Co-Authors: Rachel E J Besser, Sian Ellard, Maggie Shepherd, Timothy J Mcdonald, Beverley M Shields, Bridget A Knight, Andrew T HattersleyAbstract:OBJECTIVE Hepatocyte Nuclear Factor 1-α (HNF1A)/Hepatocyte Nuclear Factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes. RESEARCH DESIGN AND METHODS Adults with diabetes for ≥5years, without renal impairment, were studied (HNF1A MODY [ n = 54], HNF4A MODY [ n = 23], glucokinase MODY [ n = 20], type 1 diabetes [ n = 69], and type 2 diabetes [ n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes. RESULTS UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) ( P P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64). CONCLUSIONS UCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of >5 years’ duration, UCPCR could be used to determine whether genetic testing is indicated.
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mutations in the genes encoding the transcription Factors Hepatocyte Nuclear Factor 1 alpha hnf1a and 4 alpha hnf4a in maturity onset diabetes of the young
Human Mutation, 2006Co-Authors: Sian Ellard, Kevin ColcloughAbstract:Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (often <25 years of age), and pancreatic beta-cell dysfunction. MODY is both clinically and genetically heterogeneous, with six different genes identified to date; glucokinase (GCK), Hepatocyte Nuclear Factor-1 alpha (HNF1A, or TCF1), Hepatocyte Nuclear Factor-4 alpha (HNF4A), insulin promoter Factor-1 (IPF1 or PDX1), Hepatocyte Nuclear Factor-1 beta (HNF1B or TCF2), and neurogenic differentiation 1 (NEUROD1). Mutations in the HNF1A gene are a common cause of MODY in the majority of populations studied. A total of 193 different mutations have been described in 373 families. The most common mutation is Pro291fs (P291fsinsC) in the polycytosine (poly C) tract of exon 4, which has been reported in 65 families. HNF4A mutations are rarer; 31 mutations reported in 40 families. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The identification of an HNF1A or 4A gene mutation confirms a diagnosis of MODY and has important implications for clinical management.
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β cell dysfunction insulin sensitivity and glycosuria precede diabetes in Hepatocyte Nuclear Factor 1α mutation carriers
Diabetes Care, 2005Co-Authors: Amanda Stride, Sian Ellard, Penny Clark, Lynette Shakespeare, Maurice B Salzmann, Maggie Shepherd, Andrew T HattersleyAbstract:OBJECTIVE —Patients with diabetes due to Hepatocyte Nuclear Factor (HNF)-1α mutations have β-cell deficiency, insulin sensitivity, altered proinsulin levels, and a low renal threshold for glucose. It is uncertain how many of these features precede the development of diabetes. The aim of our study was to test for these characteristics in young nondiabetic HNF-1α mutation carriers. RESEARCH DESIGN AND METHODS —A total of 47 offspring from 19 extended families underwent genetic testing, a standard oral glucose tolerance test, and urine testing. RESULTS —HNF-1α mutations were found in 20 offspring, 7 with diabetes and 13 without diabetes. The 13 nondiabetic mutation carriers were compared with 27 family control subjects, who were matched for age, sex, and BMI. There was marked β-cell deficiency with reduced insulinogenic index (53.5 [31.5–90.9] vs. 226.0 [126.0–407.1], SD [range], P P P = 0.025). A total of 38% of mutation carriers had glycosuria at 2 h compared with 0% of control subjects ( P = 0.0034). Those with glycosuria had peak glucose values that were higher than the mutations carriers without glycosuria (range 8.1–11.8 vs. 6.2–8.4 mmol/l, P = 0.002). The seven subjects with diabetes all showed glycosuria. CONCLUSIONS —We conclude that marked β-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1α mutation carriers. The presence of glycosuria post–glucose load could be used to screen children of mutation carriers as it occurs in all mutation carriers with a peak glucose in the oral glucose tolerance test >8.4 mmol/l.
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mutations in Hepatocyte Nuclear Factor 1β and their related phenotypes
Journal of Medical Genetics, 2005Co-Authors: Emma L Edghill, Sian Ellard, Coralie Bingham, Andrew T HattersleyAbstract:Background: Hepatocyte Nuclear Factor-1 beta (HNF-1β) is a widely distributed transcription Factor which plays a critical role in embryonic development of the kidney, pancreas, liver, and Mullerian duct. Thirty HNF-1β mutations have been reported in patients with renal cysts and other renal developmental disorders, young-onset diabetes, pancreatic atrophy, abnormal liver function tests, and genital tract abnormalities. Methods: We sequenced the HNF-1β gene in 160 unrelated subjects with renal disease, 40% of whom had a personal/family history of diabetes. Results: Twenty three different heterozygous HNF-1β mutations were identified in 23/160 subjects (14%), including 10 novel mutations (V61G, V110G, S148L, K156E, Q176X, R276Q, S281fsinsC, R295P, H324fsdelCA, Q470X). Seven (30%) cases were proven to be due to de novo mutations. Renal cysts were found in 19/23 (83%) patients (four with glomerulocystic kidney disease, GCKD) and diabetes in 11/23 (48%, while three other families had a family history of diabetes. Only 26% of families met diagnostic criteria for maturity-onset diabetes of the young (MODY) but 39% had renal cysts and diabetes (RCAD). We found no clear genotype/phenotype relationships. Conclusion: We report the largest series to date of HNF-1β mutations and confirm HNF-1β mutations as an important cause of renal disease. Despite the original description of HNF-1β as a MODY gene, a personal/family history of diabetes is often absent and the most common clinical manifestation is renal cysts. Molecular genetic testing for HNF-1β mutations should be considered in patients with unexplained renal cysts (including GCKD), especially when associated with diabetes, early-onset gout, or uterine abnormalities.
Andrew T Hattersley - One of the best experts on this subject based on the ideXlab platform.
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urinary c peptide creatinine ratio is a practical outpatient tool for identifying Hepatocyte Nuclear Factor 1 α Hepatocyte Nuclear Factor 4 α maturity onset diabetes of the young from long duration type 1 diabetes
Diabetes Care, 2011Co-Authors: Rachel E J Besser, Sian Ellard, Maggie Shepherd, Timothy J Mcdonald, Beverley M Shields, Bridget A Knight, Andrew T HattersleyAbstract:OBJECTIVE Hepatocyte Nuclear Factor 1-α (HNF1A)/Hepatocyte Nuclear Factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes. RESEARCH DESIGN AND METHODS Adults with diabetes for ≥5years, without renal impairment, were studied (HNF1A MODY [ n = 54], HNF4A MODY [ n = 23], glucokinase MODY [ n = 20], type 1 diabetes [ n = 69], and type 2 diabetes [ n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes. RESULTS UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) ( P P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64). CONCLUSIONS UCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of >5 years’ duration, UCPCR could be used to determine whether genetic testing is indicated.
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β cell dysfunction insulin sensitivity and glycosuria precede diabetes in Hepatocyte Nuclear Factor 1α mutation carriers
Diabetes Care, 2005Co-Authors: Amanda Stride, Sian Ellard, Penny Clark, Lynette Shakespeare, Maurice B Salzmann, Maggie Shepherd, Andrew T HattersleyAbstract:OBJECTIVE —Patients with diabetes due to Hepatocyte Nuclear Factor (HNF)-1α mutations have β-cell deficiency, insulin sensitivity, altered proinsulin levels, and a low renal threshold for glucose. It is uncertain how many of these features precede the development of diabetes. The aim of our study was to test for these characteristics in young nondiabetic HNF-1α mutation carriers. RESEARCH DESIGN AND METHODS —A total of 47 offspring from 19 extended families underwent genetic testing, a standard oral glucose tolerance test, and urine testing. RESULTS —HNF-1α mutations were found in 20 offspring, 7 with diabetes and 13 without diabetes. The 13 nondiabetic mutation carriers were compared with 27 family control subjects, who were matched for age, sex, and BMI. There was marked β-cell deficiency with reduced insulinogenic index (53.5 [31.5–90.9] vs. 226.0 [126.0–407.1], SD [range], P P P = 0.025). A total of 38% of mutation carriers had glycosuria at 2 h compared with 0% of control subjects ( P = 0.0034). Those with glycosuria had peak glucose values that were higher than the mutations carriers without glycosuria (range 8.1–11.8 vs. 6.2–8.4 mmol/l, P = 0.002). The seven subjects with diabetes all showed glycosuria. CONCLUSIONS —We conclude that marked β-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1α mutation carriers. The presence of glycosuria post–glucose load could be used to screen children of mutation carriers as it occurs in all mutation carriers with a peak glucose in the oral glucose tolerance test >8.4 mmol/l.
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mutations in Hepatocyte Nuclear Factor 1β and their related phenotypes
Journal of Medical Genetics, 2005Co-Authors: Emma L Edghill, Sian Ellard, Coralie Bingham, Andrew T HattersleyAbstract:Background: Hepatocyte Nuclear Factor-1 beta (HNF-1β) is a widely distributed transcription Factor which plays a critical role in embryonic development of the kidney, pancreas, liver, and Mullerian duct. Thirty HNF-1β mutations have been reported in patients with renal cysts and other renal developmental disorders, young-onset diabetes, pancreatic atrophy, abnormal liver function tests, and genital tract abnormalities. Methods: We sequenced the HNF-1β gene in 160 unrelated subjects with renal disease, 40% of whom had a personal/family history of diabetes. Results: Twenty three different heterozygous HNF-1β mutations were identified in 23/160 subjects (14%), including 10 novel mutations (V61G, V110G, S148L, K156E, Q176X, R276Q, S281fsinsC, R295P, H324fsdelCA, Q470X). Seven (30%) cases were proven to be due to de novo mutations. Renal cysts were found in 19/23 (83%) patients (four with glomerulocystic kidney disease, GCKD) and diabetes in 11/23 (48%, while three other families had a family history of diabetes. Only 26% of families met diagnostic criteria for maturity-onset diabetes of the young (MODY) but 39% had renal cysts and diabetes (RCAD). We found no clear genotype/phenotype relationships. Conclusion: We report the largest series to date of HNF-1β mutations and confirm HNF-1β mutations as an important cause of renal disease. Despite the original description of HNF-1β as a MODY gene, a personal/family history of diabetes is often absent and the most common clinical manifestation is renal cysts. Molecular genetic testing for HNF-1β mutations should be considered in patients with unexplained renal cysts (including GCKD), especially when associated with diabetes, early-onset gout, or uterine abnormalities.
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preserved insulin response to tolbutamide in Hepatocyte Nuclear Factor 1α mutation carriers
Diabetic Medicine, 2005Co-Authors: Jørn V. Sagen, Pal R Njolstad, Oddmund Sovik, A Johansen, Oluf Pedersen, Ewan R Pearson, Ghislaine Spyer, Andrew T HattersleyAbstract:Aims Diabetic subjects with mutations in the gene encoding Hepatocyte Nuclear Factor (HNF)-1α (MODY3) are prone to develop hypoglycaemia at low doses of glibenclamide, interpreted as sulphonylurea hypersensitivity. The present study was undertaken to compare the plasma insulin responses to glucose and tolbutamide in HNF-1α mutation carriers with those of healthy control subjects. Methods Seven mutation carriers; three normoglycaemic, two with impaired glucose tolerance, and two with newly detected diabetes, underwent an oral glucose tolerance test and a tolbutamide-modified intravenous glucose tolerance test with measurements of plasma insulin. Twenty-two healthy subjects served as controls. Results The plasma insulin response to intravenous glucose was reduced in the HNF-1α mutation carriers compared to the control subjects, with an area under the curve (median (interquartile range)) of 812 min pmol/l (421, 1647) and 1933 min pmol/l (1521, 2908), respectively (P = 0.03). In striking contrast, the plasma insulin response to tolbutamide was preserved, with an area under the curve of 2109 min pmol/l (1126, 3172) and 2250 min pmol/l (1614, 3276) in the mutation carriers and control subjects, respectively. Conclusions HNF-1α mutation carriers are characterized by preserved tolbutamide-induced insulin secretion. Compared to healthy subjects, our MODY3 individuals did not show any increased serum insulin response to tolbutamide, suggesting that HNF-1α mutation carriers are not characterized by sulphonylurea hypersensitivity.
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severe hyperglycemia after renal transplantation in a pediatric patient with a mutation of the Hepatocyte Nuclear Factor 1β gene
American Journal of Kidney Diseases, 2002Co-Authors: Simon C Waller, Sian Ellard, Andrew T Hattersley, Lesley Rees, Adrian S Woolf, Ewan R Pearson, Coralie BinghamAbstract:Abstract After renal transplantation for congenital cystic kidney disease of unknown origin, a 14-year-old boy, who was previously normoglycemic, had "steroid-induced" diabetes mellitus, which was treated with insulin. Transplant failure from chronic rejection and subsequent transplant nephrectomy allowed discontinuation of corticosteroids, the gradual withdrawal of insulin and normoglycemia. The recent description of renal cysts and diabetes (RCAD) syndrome and a strong paternal family history of early-onset diabetes mellitus prompted genetic screening of the Hepatocyte Nuclear Factor-1β gene . A novel heterozygous frameshift mutation in exon 1 was identified, adding to the 12 kindreds thus far described. This case highlights the unmasking of the hyperglycemic component of the RCAD syndrome in the immediate postoperative period after renal transplantation and emphasizes the pleiotropic manifestations of this important genetic kidney disease. Am J Kidney Dis 40:1325-1330. © 2002 by the National Kidney Foundation, Inc.
Frank J Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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suppression of Hepatocyte proliferation by Hepatocyte Nuclear Factor 4α in adult mice
Journal of Biological Chemistry, 2012Co-Authors: Jessica A Bonzo, Christina H Ferry, Tsutomu Matsubara, Junghwan Kim, Frank J GonzalezAbstract:Hepatocyte Nuclear Factor 4α (HNF4α) regulates genes involved in lipid and bile acid synthesis, gluconeogenesis, amino acid metabolism, and blood coagulation. In addition to its metabolic role, HNF4α is critical for Hepatocyte differentiation, and loss of HNF4α is associated with hepatocellular carcinoma. The Hepatocyte-specific Hnf4a knock-out mouse develops severe hepatomegaly and steatosis resulting in premature death, thereby limiting studies of the role of this transcription Factor in the adult animal. In addition, gene compensation may complicate analysis of the phenotype of these mice. To overcome these issues, an acute Hnf4a knock-out mouse model was generated through use of the tamoxifen-inducible ErT2cre coupled to the serum albumin gene promoter. Microarray expression analysis revealed up-regulation of genes associated with proliferation and cell cycle control only in the acute liver-specific Hnf4α-null mouse. BrdU and ki67 staining confirmed extensive Hepatocyte proliferation in this model. Proliferation was associated with induction of the hepatomitogen Bmp7 as well as reduced basal apoptotic activity. The p53/p63 apoptosis effector gene Perp was further identified as a direct HNF4α target gene. These data suggest that HNF4α maintains Hepatocyte differentiation in the adult healthy liver, and its loss may directly contribute to hepatocellular carcinoma development, thus indicating this Factor as a possible liver tumor suppressor gene.
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Hepatocyte Nuclear Factor 1α is required for expression but dispensable for histone acetylation of the lactase phlorizin hydrolase gene in vivo
American Journal of Physiology-gastrointestinal and Liver Physiology, 2006Co-Authors: Tjalling Bosse, Frank J Gonzalez, Herbert M Van Wering, Marieke Gielen, Lauren N Dowling, John J Fialkovich, Christina M Piaseckyj, Taro E Akiyama, Robert K Montgomery, Richard J GrandAbstract:Hepatocyte Nuclear Factor-1α (HNF-1α) is a modified homeodomain-containing transcription Factor that has been implicated in the regulation of intestinal genes. To define the importance and underlyi...
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role of Hepatocyte Nuclear Factor 4α in control of blood coagulation Factor gene expression
Journal of Molecular Medicine, 2006Co-Authors: Yusuke Inoue, Luanne L Peters, Sun Hee Yim, Junko Inoue, Frank J GonzalezAbstract:Hepatocyte Nuclear Factor 4α (HNF4α) plays an important role in the maintenance of many liver-specific functions. Liver-specific HNF4α-null mice were used to determine whether hepatic HNF4α regulates blood coagulation in vivo. These mice exhibited reduced expression of hepatic coagulation Factors V, IX, XI, XII, and XIIIB and a prolonged activated partial thromboplastin time but not prothrombin time. Promoter analysis of the mouse FXII and FXIIIB genes was performed to determine whether HNF4α directly regulates the genes encoding these coagulation Factors. Sequence analysis revealed the presence of one and two HNF4α binding sites in the mouse FXII and FXIIIB genes, respectively. Using transient transfection and electrophoretic mobility shift analyses with the mouse FXII and FXIIIB promoters, it was established that the high levels of promoter activity were dependent on HNF4α binding sites and the expression of HNF4α. In conclusion, HNF4α has a critical role in blood coagulation homeostasis by directing transcription of the FXII and XIIIB genes.
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role of the Hepatocyte Nuclear Factor 4α in control of the pregnane x receptor during fetal liver development
Hepatology, 2003Co-Authors: Akihide Kamiya, Yusuke Inoue, Frank J GonzalezAbstract:Abstract The fetal liver, the major site of hematopoiesis during embryonic development, acquires additional functions near birth. Among the important liver functions is the response to xenobiotic exposure due to expression of several cytochromes P450 (CYP) and drug efflux transporters. Expression of these genes is regulated by Nuclear receptors such as the pregnane X receptor (PXR). In this study, regulation of xenobiotic responses during fetal liver development was analyzed using a fetal Hepatocyte primary culture system derived from embryonic day 15 (E15) livers. Hepatocyte Nuclear Factor (HNF) 4α regulates the expression of many genes preferentially in the liver. Expression of several xenobiotic response genes as well as HNF4α was increased in fetal Hepatocytes stimulated by the hepatic maturation Factors oncostatin M (OSM) and Matrigel. To determine the contribution of HNF4α to xenobiotic responses in the fetal liver, fetal Hepatocytes containing floxed HNF4α alleles were cultured and the HNF4α gene was inactivated by infection with an adenovirus containing the Cre gene. Expression of CYP3A11 and PXR was suppressed by inactivation of HNF4α. An HNF4α binding site was characterized in the PXR promoter and found to be required for activation of the PXR promoter in fetal Hepatocytes. In conclusion, HNF4α is the key transcription Factor regulating responses to xenobiotics through activation of the PXR gene during fetal liver development. (H epatology 2003;37:1375-1384.)
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regulation of hepatic fasting response by pparγ coactivator 1α pgc 1 requirement for Hepatocyte Nuclear Factor 4α in gluconeogenesis
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: James Rhee, Yusuke Inoue, Frank J Gonzalez, John C Yoon, Pere Puigserver, Bruce M SpiegelmanAbstract:The liver plays several critical roles in the metabolic adaptation to fasting. We have shown previously that the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1α interacts with several Nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, Hepatocyte Nuclear Factor 4α (HNF4α), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using Hepatocytes from mice lacking HNF4α in the liver, we show here that PGC-1α completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4α is absent. It is also shown that PGC-1α can induce genes of β-oxidation and ketogenesis in Hepatocytes, but these effects do not require HNF4α. Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4α-binding sites that function robustly only when HNF4α is coactivated by PGC-1α. These data illustrate the involvement of PGC-1α in several aspects of the hepatic fasting response and show that HNF4α is a critical component of PGC-1α-mediated gluconeogenesis.
Kevin Colclough - One of the best experts on this subject based on the ideXlab platform.
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mutations in the genes encoding the transcription Factors Hepatocyte Nuclear Factor 1 alpha and 4 alpha in maturity onset diabetes of the young and hyperinsulinemic hypoglycemia
Human Mutation, 2013Co-Authors: Kevin Colclough, Christine Bellannechantelot, Cecile Saintmartin, Sarah E Flanagan, Sian EllardAbstract:Maturity-onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young-onset (typically <25 years), noninsulin-dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding Hepatocyte Nuclear Factor-1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding Hepatocyte Nuclear Factor-4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ∼50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost-effective gene analysis for all patients with young onset diabetes.
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mutations in the genes encoding the transcription Factors Hepatocyte Nuclear Factor 1 alpha hnf1a and 4 alpha hnf4a in maturity onset diabetes of the young
Human Mutation, 2006Co-Authors: Sian Ellard, Kevin ColcloughAbstract:Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (often <25 years of age), and pancreatic beta-cell dysfunction. MODY is both clinically and genetically heterogeneous, with six different genes identified to date; glucokinase (GCK), Hepatocyte Nuclear Factor-1 alpha (HNF1A, or TCF1), Hepatocyte Nuclear Factor-4 alpha (HNF4A), insulin promoter Factor-1 (IPF1 or PDX1), Hepatocyte Nuclear Factor-1 beta (HNF1B or TCF2), and neurogenic differentiation 1 (NEUROD1). Mutations in the HNF1A gene are a common cause of MODY in the majority of populations studied. A total of 193 different mutations have been described in 373 families. The most common mutation is Pro291fs (P291fsinsC) in the polycytosine (poly C) tract of exon 4, which has been reported in 65 families. HNF4A mutations are rarer; 31 mutations reported in 40 families. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The identification of an HNF1A or 4A gene mutation confirms a diagnosis of MODY and has important implications for clinical management.
Stephen A Duncan - One of the best experts on this subject based on the ideXlab platform.
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Hepatocyte Nuclear Factor 4α orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Michele A Battle, Genevieve Konopka, Fereshteh Parviz, Alexandra Lerch Gaggl, Chuhu Yang, Frances M Sladek, Stephen A DuncanAbstract:Epithelial formation is a central facet of organogenesis that relies on intercellular junction assembly to create functionally distinct apical and basal cell surfaces. How this process is regulated during embryonic development remains obscure. Previous studies using conditional knockout mice have shown that loss of Hepatocyte Nuclear Factor 4α (HNF4α) blocks the epithelial transformation of the fetal liver, suggesting that HNF4α is a central regulator of epithelial morphogenesis. Although HNF4α-null Hepatocytes do not express E-cadherin (also called CDH1), we show here that E-cadherin is dispensable for liver development, implying that HNF4α regulates additional aspects of epithelial formation. Microarray and molecular analyses reveal that HNF4α regulates the developmental expression of a myriad of proteins required for cell junction assembly and adhesion. Our findings define a fundamental mechanism through which generation of tissue epithelia during development is coordinated with the onset of organ function.
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Hepatocyte Nuclear Factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis
Nature Genetics, 2003Co-Authors: Fereshteh Parviz, Christine M Matullo, Wendy Garrison, Laura Savatski, John W Adamson, Gang Ning, Klaus H Kaestner, Jennifer M Rossi, Kenneth S Zaret, Stephen A DuncanAbstract:Hepatocyte Nuclear Factor 4α controls the development of a hepatic epithelium and liver morphogenesis
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Hepatocyte Nuclear Factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis
Nature Genetics, 2003Co-Authors: Fereshteh Parviz, Christine M Matullo, Wendy Garrison, Laura Savatski, John W Adamson, Gang Ning, Klaus H Kaestner, Jennifer M Rossi, Kenneth S Zaret, Stephen A DuncanAbstract:Although advances have been made in understanding cell differentiation, only rudimentary knowledge exists concerning how differentiated cells form tissues and organs. We studied liver organogenesis because the cell and tissue architecture of this organ is well defined. Approximately 60% of the adult liver consists of Hepatocytes that are arranged as single-cell anastomosing plates extending from the portal region of the liver lobule toward the central vein. The basal surface of the Hepatocytes is separated from adjacent sinusoidal endothelial cells by the space of Disse, where the exchange of substances between serum and Hepatocytes takes place. The Hepatocyte's apical surface forms bile canaliculi that transport bile to the hepatic ducts. Proper liver architecture is crucial for hepatic function and is commonly disrupted in disease states, including cirrhosis and hepatitis. Here we report that Hepatocyte Nuclear Factor 4alpha (Hnf4alpha) is essential for morphological and functional differentiation of Hepatocytes, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4alpha is a dominant regulator of the epithelial phenotype because its ectopic expression in fibroblasts induces a mesenchymal-to-epithelial transition. Most importantly, the morphogenetic parameters controlled by Hnf4alpha in Hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium.