Hepatocyte nuclear factor 4α prevents the steatosis‐to‐NASH progression by regulating p53 and bile acid signaling

Hepatology ◽  
2020 ◽  
Author(s):  
Yanyong Xu ◽  
Yingdong Zhu ◽  
Shuwei Hu ◽  
Yang Xu ◽  
Diane Stroup ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

2005 ◽  
Vol 47 (1) ◽  
pp. 215-227 ◽  
Author(s):  
Yusuke Inoue ◽  
Ai-Ming Yu ◽  
Sun Hee Yim ◽  
Xiaochao Ma ◽  
Kristopher W. Krausz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Acid Biosynthesis ◽  
Bile Acid Biosynthesis ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals The Xenobiotic-Sensing Nuclear Receptors Pregnane X Receptor, Constitutive Androstane Receptor, and Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4α in the Regulation of Human Steroid-/Bile Acid-Sulfotransferase

2007 ◽  
Vol 21 (9) ◽  
pp. 2099-2111 ◽  
Author(s):  
Ibtissam Echchgadda ◽  
Chung S. Song ◽  
Taesung Oh ◽  
Mohamed Ahmed ◽  
Isidro John De La Cruz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Receptors ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Nuclear Factor ◽  
Orphan Nuclear Receptor ◽  
Hepatocyte Nuclear Factor ◽  
Site Mutation ◽  
Composite Element ◽  
Hepatocyte Nuclear Factor 4Α

Abstract The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are the primary transcription factors coordinating induced expression of the enzymes and proteins directing oxidative, conjugative, and transport phases of endobiotic and xenobiotic metabolism, whereas hepatocyte nuclear factor 4α (HNF4α), a regulator of hepatic lipid homeostasis, can modify the PXR/CAR response. Steroid- and bile acid-sulfotransferase (SULT2A1) promotes phase II metabolism through its sulfonating action on certain endobiotics, including steroids and bile acids, and on diverse xenobiotics, including therapeutic drugs. This study describes characterization of a PXR- and CAR-inducible composite element in the human SULT2A1 promoter and its synergistic interaction with HNF4α. Inverted and direct repeats of AG(G/T)TCA (IR2 and DR4), both binding to PXR and CAR, define the composite element. Differential recognition of the composite element by PXR and CAR is evident because single-site mutation at either IR2 or DR4 in the natural gene abolished the PXR response, whereas mutations at both repeats were necessary to abrogate completely the CAR response. The composite element conferred xenobiotic response to a heterologous promoter, and the cognate ligands induced PXR and CAR recruitment to the chromatin-associated response region. An HNF4α element adjacent to the −30 position enhanced basal promoter activity. Although functioning as a synergizer, the HNF4α element was not essential for the PXR/CAR response. An emerging role of SULT2A1 in lipid and caloric homeostasis suggests that illumination on the regulatory interactions driving human SULT2A1 expression may reveal new avenues to control certain metabolic disorders.

scholarly journals Hepatocyte Nuclear Factor 4α Is a Central Regulator of Bile Acid Conjugation

2003 ◽  
Vol 279 (4) ◽  
pp. 2480-2489 ◽  
Author(s):  
Yusuke Inoue ◽  
Ai-Ming Yu ◽  
Junko Inoue ◽  
Frank J. Gonzalez
Keyword(s):  
Bile Acid ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals Hepatocyte nuclear factor-4α and bile acids regulate human concentrative nucleoside transporter-1 gene expression

2009 ◽  
Vol 296 (4) ◽  
pp. G936-G947 ◽  
Author(s):  
Kerstin Klein ◽  
Gerd A. Kullak-Ublick ◽  
Martin Wagner ◽  
Michael Trauner ◽  
Jyrki J. Eloranta
Keyword(s):  
Gene Expression ◽  
Bile Acid ◽  
Mrna Expression ◽  
Luciferase Reporter ◽  
Nuclear Factor ◽  
Nucleoside Transporter ◽  
Hepatocyte Nuclear Factor ◽  
Expression Levels ◽  
Concentrative Nucleoside Transporter ◽  
Hepatocyte Nuclear Factor 4Α

The concentrative nucleoside transporter-1 (CNT1) is a member of the solute carrier 28 ( SLC28) gene family and is expressed in the liver, intestine, and kidneys. CNT1 mediates the uptake of naturally occurring pyrimidine nucleosides, but also nucleoside analogs used in anticancer and antiviral therapy. Thus expression levels of CNT1 may affect the pharmacokinetics of these drugs and the outcome of drug therapy. Because little is known about the transcriptional regulation of human CNT1 gene expression, we have characterized the CNT1 promoter with respect to DNA response elements and their binding factors. The transcriptional start site of the CNT1 gene was determined by 5′-RACE. In silico analysis revealed the existence of three putative binding sites for the nuclear receptor hepatocyte nuclear factor-4α (HNF-4α) within the CNT1 promoter. A luciferase reporter gene construct containing the CNT1 promoter region was transactivated by HNF-4α in human cell lines derived from the liver, intestine, and kidneys. Consistent with this, we showed in electromobility shift assays that HNF-4α specifically binds to two conserved direct repeat-1 motifs within the proximal CNT1 promoter. In cotransfection experiments, the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α further increased, whereas the bile acid-inducible corepressor small heterodimer partner reduced, HNF-4α-dependent CNT1 promoter activity. Consistent with the latter phenomenon, CNT1 mRNA expression levels were suppressed in primary human hepatocytes upon bile acid treatment. Supporting the physiological relevance and species conservation of this effect, ileal Cnt1 mRNA expression was decreased upon bile acid feeding and increased upon bile duct ligation in mice.

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