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.