Defective Pancreatic β-Cell Glycolytic Signaling in Hepatocyte Nuclear Factor-1α-deficient Mice

Dukes, I D; Sreenan, Séamus; Roe, Michael W.; Levisetti, Matteo; Zhou, Yinggang; Ostrega, Diane; Bell, Graeme I.; Pontoglio, Marco; Yaniv, Moshe; Philipson, Louis H.; Polonsky, Kenneth S.

doi:10.1074/jbc.273.38.24457

Cited by 153 publications

(125 citation statements)

References 39 publications

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“…Genetic studies have shown that mutations in HNF-1␣ result in an autosomal-dominant form of type 2 diabetes characterized by defects in pancreatic ␤-cell function and glucose-stimulated insulin release (14,23,24). In the kidney, HNF-1␣ has been shown to be a key regulator of the glucose transporter SGLT2, and haploinsufficiency of HNF-1␣ is associated with a low renal threshold for glucose that can lead to early glycosuria, even in the absence of high blood glucose levels (25,26).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Apolipoprotein M Gene Expression by MODY3 Gene Hepatocyte Nuclear Factor-1α

et al. 2003

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Hepatocyte nuclear factor-1a (HNF-1␣) is a transcription factor that plays an important role in regulation of gene expression in pancreatic ␤-cells, intestine, kidney, and liver. Heterozygous mutations in the HNF-1␣ gene are responsible for maturity-onset diabetes of the young (MODY3), which is characterized by pancreatic ␤-cell-deficient insulin secretion. HNF-1␣ is a major transcriptional regulator of many genes expressed in the liver. However, no liver defect has been identified in individuals with HNF-1␣ mutations. In this study, we show that Hnf-1␣ is a potent transcriptional activator of the gene encoding apolipoprotein M (apoM), a lipoprotein that is associated with the HDL particle. Mutant Hnf-1␣ ؊/؊ mice completely lack expression of apoM in the liver and the kidney. Serum apoM levels in Hnf-1␣ ؉/؊ mice are reduced ϳ50% compared with wild-type animals and are absent in the HDL and HDLc fractions of Hnf-1␣ ؊/؊ . We analyzed the apoM promoter and identified a conserved HNF-1 binding site. We show that Hnf-1␣ is a potent activator of the apoM promoter, that a specific mutation in the HNF-1 binding site abolished transcriptional activation of the apoM gene, and that Hnf-1␣ protein can bind to the Hnf-1 binding site of the apoM promoter in vitro. To investigate whether patients with mutations in HNF-1␣ mutations (MODY3) have reduced serum apoM levels, we measured apoM levels in the serum of nine HNF-1␣/MODY3 patients, nine normal matched control subjects (HNF-1␣ ؉/؉ ), and nine HNF-4␣/MODY1 subjects. Serum levels of apoM were decreased in HNF-1␣/MODY3 subjects when compared with control subjects (P < 0.02) as well as with HNF-4␣/MODY1 subjects, indicating that HNF-1␣ haploinsufficiency rather than hyperglycemia is the primary cause of decreased serum apoM protein concentrations. This study demonstrates that HNF-1␣ is required for apoM expression in vivo and that heterozygous HNF-1␣ mutations lead to an HNF-1␣-dependent impairment of apoM expression. ApoM levels may be a useful serum marker for the identification of MODY3 patients.

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Section: Discussionmentioning

confidence: 99%

Regulation of Apolipoprotein M Gene Expression by MODY3 Gene Hepatocyte Nuclear Factor-1α

et al. 2003

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“…Insulin promoter factor-1 (IPF1)/ MODY4, which is required for pancreatic development and insulin gene transcription, regulates the expression of the gene encoding glucokinase/MODY2. Recently, characterization of HNF-1a-knockout mice and insulinoma cells overexpressing HNF-1a and its dominant-negative mutant indicated that HNF-1a is essential for insulin gene transcription and beta-cell glycolytic signalling [2,3]. The functional relation of proteins encoded by these MODY genes suggests the importance of the HNF-transcription cascade in determining beta-cell function.…”

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Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3β and mutation screening in Japanese subjects with maturity-onset diabetes of the young

et al. 2000

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Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of early-onset Type II (non±insulin±dependent) diabetes mellitus. Five different forms of MODY have been identified [1]. Hepatocyte nuclear factor (HNF)-1a/MODY3, a homeodomain-containing transcription factor, functions as a homodimer or a heterodimer with structurally related HNF-1b/MODY5. Hepatocyte nuclear factor-4a/MODY1, a member of the nuclear receptor superfamily, is a positive regulator of HNF-1a gene transcription. Insulin promoter factor-1 (IPF1)/ MODY4, which is required for pancreatic development and insulin gene transcription, regulates the expression of the gene encoding glucokinase/MODY2. Recently, characterization of HNF-1a-knockout mice and insulinoma cells overexpressing HNF-1a and its dominant-negative mutant indicated that HNF-1a is essential for insulin gene transcription and beta-cell glycolytic signalling [2,3]. The functional relation of proteins encoded by these MODY genes suggests the importance of the HNF-transcription cascade in determining beta-cell function. Diabetologia (2000) 43: 121±124 Short communicationCloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3b and mutation screening in Japanese subjects with maturity-onset diabetes of the young Abstract Aims/hypothesis. Molecular defects of the genes for transcription factors, hepatocyte nuclear factor (HNF)-4a, HNF-1a, HNF-1b and insulin promoter factor-1 cause maturity-onset diabetes of the young (MODY1, 3, 5, and 4, respectively). This suggests the HNF-related transcription cascade is important in insulin secretion which is induced by glucose. These genes and the gene encoding glycolytic enzyme glucokinase (MODY2) are, however, responsible for only 15±20 % of cases of MODY in the Japanese. Searching for a novel form of MODY in this population, we cloned a new candidate gene encoding human HNF-3b, a winged helix transcription factor, which also belongs to the same HNF-transcription cascade. Methods. The cDNA clone for human HNF-3b was isolated from a liver cDNA library. The gene was also cloned from a genomic library and its organization and chromosomal localization were determined. We screened 68 Japanese subjects with MODY/early-onset diabetes for mutations in this gene. Results. Human HNF-3b is composed of 457 amino acids. The human gene, which was mapped to the segment 30 cR from SHGC-37 039 on chromosome 20 p by radiation hybrid mapping, spans approximately 4.5 kb and consists of three exons. Direct sequencing of the exons and flanking regions identified one missense mutation A328 V and seven polymorphisms, although the functional significance of the mutation in the pathogenesis of diabetes is not known. Conclusion/interpretation. The characterization of the structure of the HNF-3b gene and its mapping in the framework of markers will be helpful in genetic studies of the various forms of diabetes mellitus. [Diabetologia (2000) Corresponding author: J. Takeda, MD Laboratory of Molecular Genetics, Department of Cell Biology, I...

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“…A hallmark of the pathophysiology of human HNF1␣ deficiency (MODY3) and hnf1␣-null mutant mice is defective ␤ cell glucose sensing (10,11). This results at least in part from reduced aerobic glycolysis and possibly mitochondrial metabolism (12,13) although the precise molecular defects are unknown. It is likely that several islet cell-enriched genes are involved, including the glut2 glucose transporter, liver type pyruvate kinase (pklr), and aldolase B (13,14).…”

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A transcription factor regulatory circuit in differentiated pancreatic cells

Boj

Párrizas

Maestro

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

222

219

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Mutations in the human genes encoding hepatocyte nuclear factors (HNF) 1␣, 1␤, 4␣, and IPF1(PDX1͞IDX1͞STF1) result in pancreatic ␤ cell dysfunction and diabetes mellitus. In hepatocytes, hnf4␣ controls the transcription of hnf1␣, suggesting that this same interaction may operate in ␤ cells and thus account for the common diabetic phenotype. We show that, in pancreatic islet and exocrine cells, hnf4␣ expression unexpectedly depends on hnf1␣. This effect is tissue-specific and mediated through direct occupation by hnf1␣ of an alternate promoter located 45.6 kb from the previously characterized hnf4␣ promoter. Hnf1␣ also exerts direct control of pancreatic-specific expression of hnf4␥ and hnf3␥. Hnf1␣ dependence of hnf4␣, hnf4␥, hnf3␥, and two previously characterized distal targets (glut2 and pklr) is established only after differentiated cells arise during pancreatic embryonic development. These studies define an unexpected hierarchical regulatory relationship between two genes involved in human monogenic diabetes in the cells, which are relevant to its pathophysiology. Furthermore, they indicate that hnf1␣ is an essential component of a transcription factor circuit whose role may be to maintain differentiated functions of pancreatic cells.

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Defective Pancreatic β-Cell Glycolytic Signaling in Hepatocyte Nuclear Factor-1α-deficient Mice

Cited by 153 publications

References 39 publications

Regulation of Apolipoprotein M Gene Expression by MODY3 Gene Hepatocyte Nuclear Factor-1α

Regulation of Apolipoprotein M Gene Expression by MODY3 Gene Hepatocyte Nuclear Factor-1α

Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3β and mutation screening in Japanese subjects with maturity-onset diabetes of the young

A transcription factor regulatory circuit in differentiated pancreatic cells

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