Activation of the Insulin Gene Promoter through a Direct Effect of Hepatocyte Nuclear Factor 4α

Bartoov-Shifman, Reut; Hertz, Rachel; Wang, Haiyan; Wollheim, Claes B.; Bar‐Tana, Jacob; Walker, Michael D.

doi:10.1074/jbc.m201582200

Cited by 82 publications

(58 citation statements)

References 47 publications

(47 reference statements)

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“…Failure to activate transcription by missense MODY-1 mutants is ascribed to impaired dimerization, DNA binding, recruitment of coactivators, or protein destabilization (11)(12)(13)(14). MODY-1 is characterized by early onset, autosomal dominant inheritance of impaired pancreatic insulin secretion (4,18), in line with the direct (HNF-4␣/DR-1-mediated (19)) and indirect (HNF-1␣-mediated (7)) modes of transcriptional activation of the insulin gene promoter by HNF-4␣. Concomitantly, MODY-1 patients are hypolipidemic (6), in line with the profile of liver HNF-4␣-responsive genes coding for apolipoproteins (e.g.…”

Section: Hnf-4␣mentioning

confidence: 99%

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

Hertz

Ben-Haim

Petrescu

et al. 2003

Journal of Biological Chemistry

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Section: Hnf-4␣mentioning

confidence: 99%

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

Hertz

Ben-Haim

Petrescu

et al. 2003

Journal of Biological Chemistry

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“…The occupancy by HNF4α of a substantial fraction of expressed genes suggests that HNF4α is a widely acting transcription factor and crucial for development and proper secretary function of pancreatic β cells. Furthermore, BartoovShifman et al [10] found that HNF4α could activate insulin gene directly, through a previously unrecognized cis element. Clinical researches have indicated that mutations in gene encoding HNF4α result in maturityonset diabetes of the young type 1, characterized by autosomal dominant inheritance, early onset and impairment of glucose-stimulated insulin secretion (GSIS) [11] .…”

Section: Introductionmentioning

confidence: 99%

Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity

Wang¹,

Lu²,

Leng³

et al. 2008

WJG

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AIM:To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism. METHODS: Primary rat islets were isolated from male Sprague-Dawley rats by collagenase digestion and treated with different concentrations (1, 3, 10 and 30 μmol/L) of berberine or 1 μmol/L Glibenclamide (GB) for 24 h. Glucose-stimulated insulin secretion (GSIS) assay was conducted and insulin was determined by radioimmunoassay. 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to evaluate cytotoxicity. The mRNA level of hepatic nuclear factor 4 alpha (HNF4α ) was determined by reverse transcription polymerase chain reaction (RT-PCR). Indirect immunofluorescence staining and Western blot analysis were employed to detect protein expression of HNF4α in the islets. Glucokinase (GK) activity was measured by spectrophotometric method. RESULTS: Berberine enhanced GSIS rather than basal insulin secretion dose-dependently in rat islets and showed no significant cytotoxicity on islet cells at the concentration of 10 μmol/L. Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner, and GK activity was also increased accordingly. However, GB demonstrated no regulatory effects on HNF4α expression or GK activity. CONCLUSION: Berberine can enhance GSIS in rat islets, and probably exerts the insulinotropic effect via a pathway involving HNF4α and GK, which is distinct from sulphonylureas (SUs).

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“…Pdx-1 induces glucokinase, Glut2, and insulin gene expression in the mature pancreas (28,29). HNF4α regulates insulin release through controlling mitochondrial metabolism of glucose and HNF1α, Glut2, and insulin gene expression (30,31).…”

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confidence: 99%

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

Kane

Folias

Pingitore

et al. 2010

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

100

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The all-trans-retinoic acid (atRA) isomer, 9-cis-retinoic acid (9cRA), activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in vitro. RARs control multiple genes, whereas RXRs serve as partners for RARs and other nuclear receptors that regulate metabolism. Physiological function has not been determined for 9cRA, because it has not been detected in serum or multiple tissues with analytically validated assays. Here, we identify 9cRA in mouse pancreas by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and show that 9cRA decreases with feeding and after glucose dosing and varies inversely with serum insulin. 9cRA reduces glucose-stimulated insulin secretion (GSIS) in mouse islets and in the rat β-cell line 832/13 within 15 min by reducing glucose transporter type 2 (Glut2) and glucokinase (GK) activities. 9cRA also reduces Pdx-1 and HNF4α mRNA expression, ∼8-and 80-fold, respectively: defects in Pdx-1 or HNF4α cause maturity onset diabetes of the young (MODY4 and 1, respectively), as does a defective GK gene (MODY2). Pancreas β-cells generate 9cRA, and mouse models of reduced β-cell number, heterozygous Akita mice, and streptozotocin-treated mice have reduced 9cRA. 9cRA is abnormally high in glucose-intolerant mice, which have β-cell hypertropy, including mice with diet-induced obesity (DIO) and ob/ob and db/db mice. These data establish 9cRA as a pancreas-specific autacoid with multiple mechanisms of action and provide unique insight into GSIS.retinol | vitamin A | rexinoids I mpaired glucose-stimulated insulin secretion (GSIS) develops through multiple mechanisms, including actions of metabolic hormones and inflammatory cytokines, products of metabolic overload, and endoplasmic reticulum stress; however, mechanisms of GSIS and impaired glucose tolerance remain incompletely understood (1-4). Also uncertain is the contribution of impaired glucose tolerance to diminished pancreatic β-cell function and mass associated with type 2 diabetes (5). GSIS relies on the pancreas, and pancreas development, islet formation, and function require normal vitamin A nutriture (6-8). Vitamin A restriction during development impairs islet development and promotes glucose intolerance in adult rodents. On the other hand, restricting vitamin A in mature diabetes-prone rats reduces diabetes and insulitis, possibly through enhancing glucose sensing and metabolism. Alltrans-retinoic acid (atRA), an activated metabolite of vitamin A, regulates pancreas development, and atRA does not enhance the incidence of diabetes in diabetes-prone rats fed a vitamin Adeficient diet (7, 9, 10). Although the contribution of vitamin A to pancreas development through atRA seems clear, mechanisms whereby vitamin A affects mature pancreas function have not been determined in depth, nor have the specific vitamin A metabolites been identified that contribute to GSIS control.atRA induces differentiation and regulates cell processes by activating the nuclear receptors RAR α, -β, and -γ, which regulate transcription and translation (11...

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Activation of the Insulin Gene Promoter through a Direct Effect of Hepatocyte Nuclear Factor 4α

Cited by 82 publications

References 47 publications

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

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