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Hepatocyte nuclear factor-4alpha contributes to carbohydrate-induced transcriptional activation of hepatic fatty acid synthase.
- Source :
-
The Biochemical journal [Biochem J] 2006 Oct 15; Vol. 399 (2), pp. 285-95. - Publication Year :
- 2006
-
Abstract
- Refeeding a carbohydrate-rich meal after a fast produces a co-ordinated induction of key glycolytic and lipogenic genes in the liver. The transcriptional response is mediated by insulin and increased glucose oxidation, and both signals are necessary for optimal induction of FAS (fatty acid synthase). The glucose-regulated component of FAS promoter activation is mediated in part by ChREBP [ChoRE (carbohydrate response element)-binding protein], which binds to a ChoRE between -7300 and -7000 base-pairs in a carbohydrate-dependent manner. Using in vivo footprinting with nuclei from fasted and refed rats, we identify an imperfect DR-1 (direct repeat-1) element between -7110 and -7090 bp that is protected upon carbohydrate refeeding. Electrophoretic mobility-shift assays establish that this DR-1 element binds HNF-4alpha (hepatocyte nuclear factor 4alpha), and chromatin immunoprecipitation establishes that HNF-4alpha binding to this site is increased approx. 3-fold by glucose refeeding. HNF-4alpha transactivates reporter constructs containing the distal FAS promoter in a DR-1-dependent manner, and this DR-1 is required for full glucose induction of the FAS promoter in primary hepatocytes. In addition, a 3-fold knockdown of hepatocyte HNF-4alpha by small interfering RNA produces a corresponding decrease in FAS gene induction by glucose. Co-immunoprecipitation experiments demonstrate a physical interaction between HNF-4alpha and ChREBP in primary hepatocytes, further supporting an important complementary role for HNF-4alpha in glucose-induced activation of FAS transcription. Taken together, these observations establish for the first time that HNF-4alpha functions in vivo through a DR-1 element in the distal FAS promoter to enhance gene transcription following refeeding of glucose to fasted rats. The findings support the broader view that HNF-4alpha is an integral component of the hepatic nutrient sensing system that co-ordinates transcriptional responses to transitions between nutritional states.
- Subjects :
- Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism
COS Cells
Cells, Cultured
Chlorocebus aethiops
Enhancer Elements, Genetic drug effects
Enhancer Elements, Genetic genetics
Food Deprivation physiology
Hepatocytes drug effects
Humans
Liver Extracts
Male
Promoter Regions, Genetic drug effects
Promoter Regions, Genetic genetics
Protein Binding drug effects
Rats
Rats, Sprague-Dawley
Repetitive Sequences, Nucleic Acid drug effects
Repetitive Sequences, Nucleic Acid genetics
Fatty Acid Synthases metabolism
Glucose pharmacology
Hepatocyte Nuclear Factor 4 metabolism
Liver drug effects
Liver enzymology
Transcriptional Activation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8728
- Volume :
- 399
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 16800817
- Full Text :
- https://doi.org/10.1042/BJ20060659