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Review article

Hepatocyte nuclear factor-4α contributes to carbohydrate-induced transcriptional activation of hepatic fatty acid synthase

Aaron W. Adamson, Gabriela Suchankova, Caterina Rufo, Manabu T. Nakamura, Margarita Teran-Garcia, Steven D. Clarke, Thomas W. Gettys
Biochemical Journal Oct 15, 2006, 399 (2) 285-295; DOI: 10.1042/BJ20060659
Aaron W. Adamson
Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, U.S.A.
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Gabriela Suchankova
Boston Medical Center, Boston, MA 02118, U.S.A.
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Caterina Rufo
Catedra de Inmunologia, Facultad de Quimica, Universidad de la Republica, Instituto de Higiene, Montevideo, Uruguay
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Manabu T. Nakamura
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, U.S.A.
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Margarita Teran-Garcia
Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, U.S.A.
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Steven D. Clarke
McNeil Nutritionals, New Brunswick, NJ 08901, U.S.A.
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Thomas W. Gettys
Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, U.S.A.
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  • For correspondence: gettystw@pbrc.edu
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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-4α (hepatocyte nuclear factor 4α), and chromatin immunoprecipitation establishes that HNF-4α binding to this site is increased approx. 3-fold by glucose refeeding. HNF-4α 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-4α by small interfering RNA produces a corresponding decrease in FAS gene induction by glucose. Co-immunoprecipitation experiments demonstrate a physical interaction between HNF-4α and ChREBP in primary hepatocytes, further supporting an important complementary role for HNF-4α in glucose-induced activation of FAS transcription. Taken together, these observations establish for the first time that HNF-4α 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-4α is an integral component of the hepatic nutrient sensing system that co-ordinates transcriptional responses to transitions between nutritional states.

  • hepatocyte nuclear factor 4α (HNF-4α)
  • fatty acid synthase (FAS)
  • direct repeat-1 (DR-1)
  • carbohydrate response element-binding protein (ChREBP)
  • primary hepatocyte
  • transcriptional activation

Abbreviations: AOX, acyl-CoA oxidase; ChIP, chromatin immunoprecipitation; ChoRE, carbohydrate response element; ChREBP, ChoRE-binding protein; DR-1, direct repeat-1; EMSA, electrophoretic mobility-shift assay; FAS, fatty acid synthase; HEK-293, cell, human embryonic kidney cell; HNF-4α, hepatocyte nuclear factor 4α; L-PK, liver pyruvate kinase; NF-Y, nuclear factor-Y; PEPCK, phosphoenolpyruvate carboxykinase; PKA, protein kinase A; RT, reverse transcriptase; Sp1, stimulatory protein 1; SREBP, sterol-regulatory-element-binding protein; Xu-5P, xylulose 5-phosphate; siRNA, small interfering RNA

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October 2006

Volume: 399 Issue: 2

Biochemical Journal: 399 (2)
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Hepatocyte nuclear factor-4α contributes to carbohydrate-induced transcriptional activation of hepatic fatty acid synthase
Aaron W. Adamson, Gabriela Suchankova, Caterina Rufo, Manabu T. Nakamura, Margarita Teran-Garcia, Steven D. Clarke, Thomas W. Gettys
Biochemical Journal Oct 2006, 399 (2) 285-295; DOI: 10.1042/BJ20060659
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Hepatocyte nuclear factor-4α contributes to carbohydrate-induced transcriptional activation of hepatic fatty acid synthase
Aaron W. Adamson, Gabriela Suchankova, Caterina Rufo, Manabu T. Nakamura, Margarita Teran-Garcia, Steven D. Clarke, Thomas W. Gettys
Biochemical Journal Oct 2006, 399 (2) 285-295; DOI: 10.1042/BJ20060659

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Keywords

hepatocyte nuclear factor 4α (HNF-4α)
fatty acid synthase (FAS)
direct repeat-1 (DR-1)
carbohydrate response element-binding protein (ChREBP)
primary hepatocyte
transcriptional activation

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