The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion

Gupta, Rana K.; Vatamaniuk, Marko Z.; Lee, Catherine S.; Flaschen, Reed C.; Fulmer, James; Matschinsky, Franz M.; Duncan, Stephen A.; Kaestner, Klaus H.

doi:10.1172/jci200522365

Cited by 201 publications

(174 citation statements)

References 56 publications

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“…HNF4␣ is highly expressed in liver, kidney, intestine, and pancreas, and its crucial role in liver and endocrine pancreas has been demonstrated by genome-wide expression profiling (2) and conditional deletion in mice (3)(4)(5)(6). In addition, dysfunction of HNF4␣ is associated with various metabolic disorders, and mutations in HNF4␣ cause a dominantly inherited form of diabetes referred to as MODY1 (maturity-onset diabetes of the young) (7).…”

Section: Hepatocyte Nuclear Factor 4␣ (Hnf4␣)mentioning

confidence: 99%

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

Rha

Shoelson

et al. 2009

Journal of Biological Chemistry

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Hepatocyte nuclear factor 4␣ (HNF4␣) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4␣ interacts, peroxisome proliferation-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/ p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1␣ recruitment, we have determined the crystal structure of HNF4␣ in complex with a fragment of PGC-1␣ containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4␣ toward the LXXLL motifs of PGC-1␣ could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators.

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Section: Hepatocyte Nuclear Factor 4␣ (Hnf4␣)mentioning

confidence: 99%

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

Rha

Shoelson

et al. 2009

Journal of Biological Chemistry

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“…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] . And two independent laboratory studies demonstrated that β-cell-specific HNF4α knock-out mice exhibited impaired GSIS and deficient intracellular calcium response to glucose or SU [12,13] .…”

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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“…Decreased activity of K ATP or Kv2.1 in islets increases insulin secretion (19), suggesting that these channels may mediate propafenone's effects on insulin secretion. Although amiloride and propafenone have not been previously studied in the context of HNF4α, SCNN1A (encoding the target of amiloride) and KCNJ11 (encoding Kir6.2, a subunit of K ATP ) are among the hundreds of reported transcriptional targets of HNF4α (though data on the dependence of KCNJ11 expression on HNF4α in vivo are conflicting) (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

“…HNF4α binds to upstream sequences of hundreds of genes involved in glucose, lipid, cholesterol, amino acid, and drug metabolism (8)(9)(10). Two different conditional knockouts of HNF4α in β-cells yielded conflicting phenotypes: although both knockout models showed impaired insulin secretion in response to glucose challenge (11,12), one model also unexpectedly showed elevated resting insulin levels with associated hypoglycemia (12), highlighting our incomplete understanding of the physiologic effects of HNF4α mutation.…”

mentioning

confidence: 99%

Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes

Shaw

Blodgett²,

Maggie³

et al. 2010

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

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Even as genetic studies identify alleles that influence human disease susceptibility, it remains challenging to understand their functional significance and how they contribute to disease phenotypes. Here, we describe an approach to translate discoveries from human genetics into functional and therapeutic hypotheses by relating human genetic variation to small-molecule sensitivities. We use small-molecule probes modulating a breadth of targets and processes to reveal disease allele-dependent sensitivities, using cells from multiple individuals with an extreme form of diabetes (maturity onset diabetes of the young type 1, caused by mutation in the orphan nuclear receptor HNF4α). This approach enabled the discovery of small molecules that show mechanistically revealing and therapeutically relevant interactions with HNF4α in both lymphoblasts and pancreatic β-cells, including compounds that physically interact with HNF4α. Compounds including US Food and Drug Administration–approved drugs were identified that favorably modulate a critical disease phenotype, insulin secretion from β-cells. This method may suggest therapeutic hypotheses for other nonblood disorders.

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The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion

Cited by 201 publications

References 56 publications

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

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

Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes

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