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.
Highlights
Hepatocyte nuclear factor-1α (HNF-1α) is a transcription factor that was originally thought to only be expressed in the liver, but has been found to be expressed in the kidneys, pancreas, intestines, stomach, spleen, thymus, testis, and keratinocytes and melanocytes in human skin
Computational molecular docking of various berry phenolic compounds and citrus flavonoids to the dimerization domain and transcription domain of HNF-1α showed that anthocyanins and anthocyanidins, commonly found in berries, had on average more interactions and a higher affinity than resveratrol and the citrus flavonoids studied
Delphinidin-3-O-arabinoside had the highest affinity for the transcription domain of HNF-1α, indicating that it is most likely to interact with this domain of HNF-1α as compared to the other compounds tested
Summary
Hepatocyte nuclear factor-1α (HNF-1α) is a transcription factor that was originally thought to only be expressed in the liver, but has been found to be expressed in the kidneys, pancreas, intestines, stomach, spleen, thymus, testis, and keratinocytes and melanocytes in human skin. It is composed of a dimerization domain (residues 1–32), a transcription domain (residues 203–276), and a transactivation domain (residues 281–631) [1]. HNF-1α has been recently shown to be involved in GLUT1 and GLUT2 transporter expression in pancreatic β-cells [6] and angiotensin-converting enzyme 2 gene expression in pancreatic islets [7]
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