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Review
. 2016 Sep;6(5):393-408.
doi: 10.1016/j.apsb.2016.07.003. Epub 2016 Jul 28.

Crosstalk of HNF4 α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids

Hong Lu  1
Affiliations
Review

Crosstalk of HNF4 α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids

Hong Lu. Acta Pharm Sin B. 2016 Sep.

Abstract

The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis. Metabolism of xenobiotics, such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics, whereas metabolism of cholesterol, bile acids (BAs), lipids, and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism. As a well-established master regulator of liver development and function, hepatocyte nuclear factor 4 alpha (HNF4α) plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics, metabolic wastes, and nutrients. The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone, glucocorticoids, thyroid hormone, insulin, transforming growth factor-β, estrogen, and cytokines. HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver. There have been a few reviews on the regulation of drug metabolism, lipid metabolism, cell proliferation, and inflammation by HNF4α. However, the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered. Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α, and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.

Keywords: Drug metabolism; HNF4α; Hormone; Inflammation; Lipid metabolism; Liver.

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Figures

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Graphical abstract
Fig. 1
Figure 1
Diagrams that illustrate the protein domain structure (A), posttranslational modifications (B), and interactions (C) of HNF4α with other signaling pathways. (A) Domain structure of HNF4α protein, with the 474-amino-acid-long human HNF4α2 shown as the canonical HNF4α isoform. (B) Posttranslational modifications of HNF4α. HNF4α is methylated at arginine 100 (R100M) by PRMT1, and acetylated at lysines 106, 108, 118, or 119 by CBP. HNF4α is phosphorylated at lysine-23 (Y23P) and Y286 (Y286P) by c-SRC, serine 87 (S87P) by PKC, serine 142 and 143 (S142P and S143P) by PKA, serine 167 (S167P) by P38, and serine 313 (S313P) by AMPK. The positions of post-translational modifications of HNF4α have been renumbered in the text and Fig. 1 based on the updated NCBI protein database for HNF4α2 (NP_000448.3), which is also used as the canonical protein isoform for human HNF4α in PhosphoSitePlus®, a public database for posttranslational modifications of proteins. (C) Transcriptional factors that modulate the transcriptional activity of HNF4α through physical interactions. Red shape: negative interaction; purple shape: both negative and positive interactions; green shape: positive interaction.
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References

    1. Li J.X., Ning G., Duncan S.A. Mammalian hepatocyte differentiation requires the transcription factor HNF-4α. Genes Dev. 2000;14:464–474. - PMC - PubMed
    1. Kyrmizi I., Hatzis P., Katrakili N., Tronche F., Gonzalez F.J., Talianidis I. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev. 2006;20:2293–2305. - PMC - PubMed
    1. Hayhurst G.P., Lee Y.H., Lambert G., Ward J.M., Gonzalez F.J. Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol. 2001;21:1393–1403. - PMC - PubMed
    1. Gonzalez F.J. Regulation of hepatocyte nuclear factor 4α-mediated transcription. Drug Metab Pharmacokinet. 2008;23:2–7. - PubMed
    1. Hwang-Verslues W.W., Sladek F.M. HNF4α—role in drug metabolism and potential drug target? Curr Opin Pharmacol. 2010;10:698–705. - PMC - PubMed

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