Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 290, Issue 3, Pages G466-G475Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00431.2005
Keywords
transcription factor; hepatic nuclear factor-4; hepatic nuclear factor-1
Categories
Funding
- NIDDK NIH HHS [DK-56361, DK-20579, DK-52574] Funding Source: Medline
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Hepatic nuclear factor (HNF)-4 alpha and HNF-1 alpha are key endodermal transcriptional regulators that physically and functionally interact. HNF-4 alpha and HNF-1 alpha cooperatively activate genes with binding sites for both factors, whereas suppressive interactions occur at regulatory sequences with a binding site for only one factor. The liver fatty acid binding protein gene (Fabp1) has binding sites for both factors, and chromatin precipitation assays were utilized to demonstrate that HNF-4 alpha increased HNF-1 alpha Fabp1 promoter occupancy during cooperative transcriptional activation. The HNF4 P2 promoter contains a HNF-1 but not HNF-4 binding site, and HNF-4 alpha suppressed HNF-1 alpha HNF4 P2 activation and decreased promoter HNF-1 alpha occupancy. The apolipoprotein C III (APOC3) promoter contains a HNF-4 but not HNF-1 binding site, and HNF-1 alpha suppressed HNF-4 alpha APOC3 activation and decreased HNF-4 alpha promoter occupancy. Maturity onset diabetes of the young ( MODY) as well as defects in hepatic lipid metabolism result from mutations in either HNF-4 alpha or HNF-1 alpha. We found that MODY missense mutant R127W HNF-4 alpha retained wildtype individual Fabp1 activation and bound to HNF-1 alpha better than wild- type HNF-4 alpha, yet did not cooperate with HNF-1 alpha or increase HNF-1 alpha Fabp1 promoter occupancy. The R127W mutant was also defective in both suppressing HNF-1 alpha activation of HNF4 P2 and decreasing HNF-1 alpha promoter occupancy. The HNF-1 alpha R131Q MODY mutant also retained wild- type Fabp1 activation and bound to HNF-4 alpha as well as the wild type but was defective in both suppressing HNF-4 alpha APOC3 activation and decreasing HNF-4 alpha promoter occupancy. These results suggest HNF-1 alpha- HNF-4 alpha functional interactions are accomplished by regulating factor promoter occupancy and that defective factor- factor interactions may contribute to the MODY phenotype.
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