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Berry Phenolic Compounds Increase Expression of Hepatocyte Nuclear Factor-1α (HNF-1α) in Caco-2 and Normal Colon Cells Due to High Affinities with Transcription and Dimerization Domains of HNF-1α.

Real Hernandez LM, Fan J, Johnson MH, Gonzalez de Mejia E - PLoS ONE (2015)

Bottom Line: All extracts tested increased significantly (P < 0.05) the nuclear expression of HNF-1α in Caco-2 cells by 85.2 to 260% compared to a control.The extracts tested increased significantly (P < 0.02) the nuclear expression of HNF-1α in normal colon cells by 48.6 to 243%.Anthocyanins significantly increased nuclear HNF-1α expression, suggesting that these compounds might regulate the genes HNF-1α promotes.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, United States of America; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, United States of America.

ABSTRACT
Hepatocyte nuclear factor-1α (HNF-1α) is found in the kidneys, spleen, thymus, testis, skin, and throughout the digestive organs. It has been found to promote the transcription of various proteins involved in the management of type II diabetes, including dipeptidyl peptidase-IV (DPP-IV). Phenolic compounds from berries and citrus fruits are known to inhibit DPP-IV, but have not been tested for their interactions with wild-type HNF-1α. By studying the interactions of compounds from berries and citrus fruits have with HNF-1α, pre-transcriptional mechanisms that inhibit the expression of proteins such as DPP-IV may be elucidated. In this study, the interactions of berry phenolic compounds and citrus flavonoids with the dimerization and transcriptional domains of HNF-1α were characterized using the molecular docking program AutoDock Vina. The anthocyanin delphinidin-3-O-arabinoside had the highest binding affinity for the dimerization domain as a homodimer (-7.2 kcal/mol) and transcription domain (-8.3 kcal/mol) of HNF-1α. Anthocyanins and anthocyanidins had relatively higher affinities than resveratrol and citrus flavonoids for both, the transcription domain and the dimerization domain as a homodimer. The flavonoid flavone had the highest affinity for a single unit of the dimerization domain (-6.5 kcal/mol). Nuclear expression of HNF-1α was measured in Caco-2 and human normal colon cells treated with blueberry and blackberry anthocyanin extracts. All extracts tested increased significantly (P < 0.05) the nuclear expression of HNF-1α in Caco-2 cells by 85.2 to 260% compared to a control. The extracts tested increased significantly (P < 0.02) the nuclear expression of HNF-1α in normal colon cells by 48.6 to 243%. It was confirmed that delphinidin-3-O-glucoside increased by 3-fold nuclear HNF-1α expression in Caco-2 cells (P < 0.05). Anthocyanins significantly increased nuclear HNF-1α expression, suggesting that these compounds might regulate the genes HNF-1α promotes.

No MeSH data available.


Related in: MedlinePlus

Validation study by re-docking myristic acid to hepatocyte nuclear factor-4α (HNF-4α).The interactions that myristic acid has with HNF-4α in PDB file 4IQR are shown (A) alongside the interactions the best experimental docking conformation of myristic acid had with the same structure (B). Amino acids from HNF-4α that interacted with myristic acid in each conformation either had electrostatic (pink) or van der Waals (green) interactions. Hydrogen bonds are shown as one headed, dashed arrows formed with amino acid main-chain (green) or side-chain (blue) atoms, while pink double headed, dashed arrows represent charged interactions. The area of interaction both myristic acid conformations had with HNF-4α (C) is shown alongside a comparison of both the experimental conformation (orange) and the conformation (red) found in PDB file 4IQR (D). A lilac surface around both conformations (C, D) represents a general surface of HNF-4α.
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pone.0138768.g005: Validation study by re-docking myristic acid to hepatocyte nuclear factor-4α (HNF-4α).The interactions that myristic acid has with HNF-4α in PDB file 4IQR are shown (A) alongside the interactions the best experimental docking conformation of myristic acid had with the same structure (B). Amino acids from HNF-4α that interacted with myristic acid in each conformation either had electrostatic (pink) or van der Waals (green) interactions. Hydrogen bonds are shown as one headed, dashed arrows formed with amino acid main-chain (green) or side-chain (blue) atoms, while pink double headed, dashed arrows represent charged interactions. The area of interaction both myristic acid conformations had with HNF-4α (C) is shown alongside a comparison of both the experimental conformation (orange) and the conformation (red) found in PDB file 4IQR (D). A lilac surface around both conformations (C, D) represents a general surface of HNF-4α.

Mentions: The resulting root-mean-square deviation (RMSD) of all heavy atoms in the conformation of myristic acid in the hepatocyte nuclear factor-4α (HNF-4α) crystal structure of The RCSB Protein Data Bank (PDB) file 4IQR, compared to the resulting myristic acid experimental conformation from AutoDock Vina, was 1.458 angstroms using the match function from the USFC Chimera package. Both conformations had nine exact amino acid interactions (Fig 5A and 5B) (VAL178, SER181, MET182, LEU219, ALA223, ARG226, LEU236, GLY237, MET252) within the same location of HNF-4α (Fig 5C) given the large search space parameters. The conformations can be compared visually in Fig 5D. Both conformations show myristic acid having hydrogen bonds with HNF-4α amino acids SER181, ARG226, and GLY237 (Fig 5A and 5B). The charged interaction between ARG226 and myristic acid in PDB file 4IQR is not observed in the experimental conformation from AutoDock Vina, instead a second hydrogen bond with ARG226 is observed. A van der Waals interaction with GLN185 is observed in PDB file 4IQR while an electrostatic interaction with the same amino acid resulted in the experimental conformation. Given the similarity between the known and experimental conformations of myristic acid, the computational methodology used showed to produce conformations similar to those found in known structures, and was therefore used in this study.


Berry Phenolic Compounds Increase Expression of Hepatocyte Nuclear Factor-1α (HNF-1α) in Caco-2 and Normal Colon Cells Due to High Affinities with Transcription and Dimerization Domains of HNF-1α.

Real Hernandez LM, Fan J, Johnson MH, Gonzalez de Mejia E - PLoS ONE (2015)

Validation study by re-docking myristic acid to hepatocyte nuclear factor-4α (HNF-4α).The interactions that myristic acid has with HNF-4α in PDB file 4IQR are shown (A) alongside the interactions the best experimental docking conformation of myristic acid had with the same structure (B). Amino acids from HNF-4α that interacted with myristic acid in each conformation either had electrostatic (pink) or van der Waals (green) interactions. Hydrogen bonds are shown as one headed, dashed arrows formed with amino acid main-chain (green) or side-chain (blue) atoms, while pink double headed, dashed arrows represent charged interactions. The area of interaction both myristic acid conformations had with HNF-4α (C) is shown alongside a comparison of both the experimental conformation (orange) and the conformation (red) found in PDB file 4IQR (D). A lilac surface around both conformations (C, D) represents a general surface of HNF-4α.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4587667&req=5

pone.0138768.g005: Validation study by re-docking myristic acid to hepatocyte nuclear factor-4α (HNF-4α).The interactions that myristic acid has with HNF-4α in PDB file 4IQR are shown (A) alongside the interactions the best experimental docking conformation of myristic acid had with the same structure (B). Amino acids from HNF-4α that interacted with myristic acid in each conformation either had electrostatic (pink) or van der Waals (green) interactions. Hydrogen bonds are shown as one headed, dashed arrows formed with amino acid main-chain (green) or side-chain (blue) atoms, while pink double headed, dashed arrows represent charged interactions. The area of interaction both myristic acid conformations had with HNF-4α (C) is shown alongside a comparison of both the experimental conformation (orange) and the conformation (red) found in PDB file 4IQR (D). A lilac surface around both conformations (C, D) represents a general surface of HNF-4α.
Mentions: The resulting root-mean-square deviation (RMSD) of all heavy atoms in the conformation of myristic acid in the hepatocyte nuclear factor-4α (HNF-4α) crystal structure of The RCSB Protein Data Bank (PDB) file 4IQR, compared to the resulting myristic acid experimental conformation from AutoDock Vina, was 1.458 angstroms using the match function from the USFC Chimera package. Both conformations had nine exact amino acid interactions (Fig 5A and 5B) (VAL178, SER181, MET182, LEU219, ALA223, ARG226, LEU236, GLY237, MET252) within the same location of HNF-4α (Fig 5C) given the large search space parameters. The conformations can be compared visually in Fig 5D. Both conformations show myristic acid having hydrogen bonds with HNF-4α amino acids SER181, ARG226, and GLY237 (Fig 5A and 5B). The charged interaction between ARG226 and myristic acid in PDB file 4IQR is not observed in the experimental conformation from AutoDock Vina, instead a second hydrogen bond with ARG226 is observed. A van der Waals interaction with GLN185 is observed in PDB file 4IQR while an electrostatic interaction with the same amino acid resulted in the experimental conformation. Given the similarity between the known and experimental conformations of myristic acid, the computational methodology used showed to produce conformations similar to those found in known structures, and was therefore used in this study.

Bottom Line: All extracts tested increased significantly (P < 0.05) the nuclear expression of HNF-1α in Caco-2 cells by 85.2 to 260% compared to a control.The extracts tested increased significantly (P < 0.02) the nuclear expression of HNF-1α in normal colon cells by 48.6 to 243%.Anthocyanins significantly increased nuclear HNF-1α expression, suggesting that these compounds might regulate the genes HNF-1α promotes.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, United States of America; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, United States of America.

ABSTRACT
Hepatocyte nuclear factor-1α (HNF-1α) is found in the kidneys, spleen, thymus, testis, skin, and throughout the digestive organs. It has been found to promote the transcription of various proteins involved in the management of type II diabetes, including dipeptidyl peptidase-IV (DPP-IV). Phenolic compounds from berries and citrus fruits are known to inhibit DPP-IV, but have not been tested for their interactions with wild-type HNF-1α. By studying the interactions of compounds from berries and citrus fruits have with HNF-1α, pre-transcriptional mechanisms that inhibit the expression of proteins such as DPP-IV may be elucidated. In this study, the interactions of berry phenolic compounds and citrus flavonoids with the dimerization and transcriptional domains of HNF-1α were characterized using the molecular docking program AutoDock Vina. The anthocyanin delphinidin-3-O-arabinoside had the highest binding affinity for the dimerization domain as a homodimer (-7.2 kcal/mol) and transcription domain (-8.3 kcal/mol) of HNF-1α. Anthocyanins and anthocyanidins had relatively higher affinities than resveratrol and citrus flavonoids for both, the transcription domain and the dimerization domain as a homodimer. The flavonoid flavone had the highest affinity for a single unit of the dimerization domain (-6.5 kcal/mol). Nuclear expression of HNF-1α was measured in Caco-2 and human normal colon cells treated with blueberry and blackberry anthocyanin extracts. All extracts tested increased significantly (P < 0.05) the nuclear expression of HNF-1α in Caco-2 cells by 85.2 to 260% compared to a control. The extracts tested increased significantly (P < 0.02) the nuclear expression of HNF-1α in normal colon cells by 48.6 to 243%. It was confirmed that delphinidin-3-O-glucoside increased by 3-fold nuclear HNF-1α expression in Caco-2 cells (P < 0.05). Anthocyanins significantly increased nuclear HNF-1α expression, suggesting that these compounds might regulate the genes HNF-1α promotes.

No MeSH data available.


Related in: MedlinePlus