Rescue of MODY-1 by agonist ligands of hepatocyte nuclear factor-4α

Rachel Hertz; Nadav Ben-Haim; Anca D. Petrescu; Bella Kalderon; Inna Berman; Naama Eldad; Friedhelm Schroeder; Jacob Bar-Tana

doi:10.1074/jbc.M212138200

Rescue of MODY-1 by agonist ligands of hepatocyte nuclear factor-4α

Rachel Hertz, Nadav Ben-Haim, Anca D. Petrescu, Bella Kalderon, Inna Berman, Naama Eldad, Friedhelm Schroeder, Jacob Bar-Tana^*

^*Corresponding author for this work

Braun School of Public Health and Community Medicine

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Missense mutations of the ligand binding domain of hepatocyte nuclear factor (HNF)-4α result in maturity onset diabetes of the young (MODY)-1. We show here that MODY-1 as well as Gln-185 missense mutants of the ligand binding domain of HNF-4α fail to transactivate transcription of HNF-4α-responsive genes. Defective transactivation by these mutants is accounted for by their reduced binding affinities for fatty acyl agonist ligands of HNF-4α. These mutants may be rescued by exogenous fatty acid agonist ligands of HNF-4α, yielding transcriptional activities in the wild type range. The effect of added ligands is synergistic with that of transcriptional coactivators of HNF-4α. These findings may indicate the means for treating selected MODY-1 subjects with HNF-4α agonist nutrients and drugs.

Original language	English
Pages (from-to)	22578-22585
Number of pages	8
Journal	Journal of Biological Chemistry
Volume	278
Issue number	25
DOIs	https://doi.org/10.1074/jbc.M212138200
State	Published - 20 Jun 2003

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title = "Rescue of MODY-1 by agonist ligands of hepatocyte nuclear factor-4α",

abstract = "Missense mutations of the ligand binding domain of hepatocyte nuclear factor (HNF)-4α result in maturity onset diabetes of the young (MODY)-1. We show here that MODY-1 as well as Gln-185 missense mutants of the ligand binding domain of HNF-4α fail to transactivate transcription of HNF-4α-responsive genes. Defective transactivation by these mutants is accounted for by their reduced binding affinities for fatty acyl agonist ligands of HNF-4α. These mutants may be rescued by exogenous fatty acid agonist ligands of HNF-4α, yielding transcriptional activities in the wild type range. The effect of added ligands is synergistic with that of transcriptional coactivators of HNF-4α. These findings may indicate the means for treating selected MODY-1 subjects with HNF-4α agonist nutrients and drugs.",

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AU - Hertz, Rachel

AU - Ben-Haim, Nadav

AU - Petrescu, Anca D.

AU - Kalderon, Bella

AU - Berman, Inna

AU - Eldad, Naama

AU - Schroeder, Friedhelm

AU - Bar-Tana, Jacob

PY - 2003/6/20

Y1 - 2003/6/20

N2 - Missense mutations of the ligand binding domain of hepatocyte nuclear factor (HNF)-4α result in maturity onset diabetes of the young (MODY)-1. We show here that MODY-1 as well as Gln-185 missense mutants of the ligand binding domain of HNF-4α fail to transactivate transcription of HNF-4α-responsive genes. Defective transactivation by these mutants is accounted for by their reduced binding affinities for fatty acyl agonist ligands of HNF-4α. These mutants may be rescued by exogenous fatty acid agonist ligands of HNF-4α, yielding transcriptional activities in the wild type range. The effect of added ligands is synergistic with that of transcriptional coactivators of HNF-4α. These findings may indicate the means for treating selected MODY-1 subjects with HNF-4α agonist nutrients and drugs.

AB - Missense mutations of the ligand binding domain of hepatocyte nuclear factor (HNF)-4α result in maturity onset diabetes of the young (MODY)-1. We show here that MODY-1 as well as Gln-185 missense mutants of the ligand binding domain of HNF-4α fail to transactivate transcription of HNF-4α-responsive genes. Defective transactivation by these mutants is accounted for by their reduced binding affinities for fatty acyl agonist ligands of HNF-4α. These mutants may be rescued by exogenous fatty acid agonist ligands of HNF-4α, yielding transcriptional activities in the wild type range. The effect of added ligands is synergistic with that of transcriptional coactivators of HNF-4α. These findings may indicate the means for treating selected MODY-1 subjects with HNF-4α agonist nutrients and drugs.

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Rescue of MODY-1 by agonist ligands of hepatocyte nuclear factor-4α

Abstract

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