Elevated Levels of Hepatocyte Nuclear Factor 3β in Mouse Hepatocytes Influence Expression of Genes Involved in Bile Acid and Glucose Homeostasis

2000 ◽  
Vol 20 (21) ◽  
pp. 8264-8282 ◽  
Author(s):  
Francisco M. Rausa ◽  
Yongjun Tan ◽  
Heping Zhou ◽  
Kyung W. Yoo ◽  
Donna Beer Stolz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Glucose Homeostasis ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Expression Of Genes ◽  
Mouse Hepatocytes

scholarly journals Elevated Levels of Hepatocyte Nuclear Factor 3β in Mouse Hepatocytes Influence Expression of Genes Involved in Bile Acid and Glucose Homeostasis

2000 ◽  
Vol 20 (21) ◽  
pp. 8264-8282 ◽  
Author(s):  
Francisco M. Rausa ◽  
Yongjun Tan ◽  
Heping Zhou ◽  
Kyung W. Yoo ◽  
Donna Beer Stolz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Transgenic Mice ◽  
Bile Acids ◽  
Glucose Homeostasis ◽  
Postnatal Growth ◽  
Glycogen Storage ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatic Expression

ABSTRACT The winged helix transcription factor, hepatocyte nuclear factor-3β (HNF-3β), mediates the hepatocyte-specific transcription of numerous genes important for liver function. However, the in vivo role of HNF-3β in regulating these genes remains unknown because homozygous null HNF3β mouse embryos die in utero prior to liver formation. In order to examine the regulatory function of HNF-3β, we created transgenic mice in which the −3-kb transthyretin promoter functions to increase hepatocyte expression of the rat HNF-3β protein. Postnatal transgenic mice exhibit growth retardation, depletion of hepatocyte glycogen storage, and elevated levels of bile acids in serum. The retarded growth phenotype is likely due to a 20-fold increase in hepatic expression of insulin-like growth factor binding protein 1 (IGFBP-1), which results in elevated levels in serum of IGFBP-1 and limits the biological availability of IGFs required for postnatal growth. The defects in glycogen storage and serum bile acids coincide with diminished postnatal expression of hepatocyte genes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase and glycogen synthase) and sinusoidal bile acid uptake (Ntcp), respectively. These changes in gene transcription may result from the disruptive effect of HNF-3β on the hepatic expression of the endogenous mouse HNF-3α,-3β, -3γ, and -6 transcription factors. Furthermore, adult transgenic livers lack expression of the canalicular phospholipid transporter, mdr2, which is consistent with ultrastructure evidence of damage to transgenic hepatocytes and bile canaliculi. These transgenic studies represent the first in vivo demonstration that the HNF-3β transcriptional network regulates expression of hepatocyte-specific genes required for bile acid and glucose homeostasis, as well as postnatal growth.

scholarly journals Hepatocyte Nuclear Factor 1, a Transcription Factor at the Crossroads of Glucose Homeostasis

2000 ◽  
Vol 11 (suppl 2) ◽  
pp. S140-S143
Author(s):  
MARCO PONTOGLIO
Keyword(s):  
Transcription Factor ◽  
Glucose Homeostasis ◽  
Phenylalanine Hydroxylase ◽  
Large Set ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Expression Of Genes ◽  
Proximal Tubular ◽  
Renal Proximal Tubular ◽  
Nuclear Factor 1

Abstract. Hepatocyte nuclear factor 1 (HNF1) is a transcription factor involved in the regulation of a large set of hepatic genes, including albumin, β-fibrinogen, and α1-antitrypsin. HNF1 is expressed in the liver, digestive tract, pancreas, and kidney. Mice lacking HNF1 exhibit hepatic, pancreatic, and renal dysfunctions. HNF1-deficient mice fail to express the hepatic phenylalanine hydroxylase gene, giving rise to hyperphenylalaninemia. Renal proximal tubular reabsorption of glucose, phosphate, arginine, and other metabolites is affected, producing severe renal glucosuria, phosphaturia, and amino aciduria. Homozygous mutant mice also exhibit a dramatic insulin secretion defect. This dysfunction resembles that exhibited by patients with maturity-onset diabetes mellitus of the young type 3, who carry mutations in the human HNF1 gene in the heterozygous state. These data show that HNF1 is a major regulator of glucose homeostasis, regulating the expression of genes that are expressed in the liver, kidney, and pancreas.

scholarly journals Hepatocyte Nuclear Factor 4α (Nuclear Receptor 2A1) Is Essential for Maintenance of Hepatic Gene Expression and Lipid Homeostasis

2001 ◽  
Vol 21 (4) ◽  
pp. 1393-1403 ◽  
Author(s):  
Graham P. Hayhurst ◽  
Ying-Hue Lee ◽  
Gilles Lambert ◽  
Jerrold M. Ward ◽  
Frank J. Gonzalez
Keyword(s):  
Bile Acid ◽  
Nuclear Receptor ◽  
Density Lipoprotein ◽  
Lipid Homeostasis ◽  
Transcriptional Level ◽  
Serum Bile Acid ◽  
Acid Uptake ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Differentiation

ABSTRACT The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1α [HNF1α], -1β, -3α, -3β, -3γ, -4α, and -6 and members of the c/ebp family). Of these, only HNF4α (nuclear receptor 2A1) and HNF1α appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1α-null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4α-null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4α is indispensable for hepatocyte differentiation. However, the function of HNF4α in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4α in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4α expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4α is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.

scholarly journals Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)–Deficient Mice

Diabetes ◽  
2015 ◽  
Vol 64 (9) ◽  
pp. 3314-3320 ◽  
Author(s):  
François Brial ◽  
Carine R. Lussier ◽  
Karine Belleville ◽  
Philippe Sarret ◽  
François Boudreau
Keyword(s):  
Glucose Homeostasis ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 1Α ◽  
Deficient Mice

scholarly journals Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1α

2007 ◽  
Vol 402 (1) ◽  
pp. 81-91 ◽  
Author(s):  
Guillaume Piessen ◽  
Nicolas Jonckheere ◽  
Audrey Vincent ◽  
Brigitte Hémon ◽  
Marie-Paule Ducourouble ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Bile Acid ◽  
Bile Acids ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Cis Elements ◽  
Muc4 Expression ◽  
Hepatocyte Nuclear Factor 1Α ◽  
Distal Promoter

MUC4 (mucin 4) is a membrane-bound mucin overexpressed in the early steps of oesophageal carcinogenesis and implicated in tumour progression. We previously showed that bile acids, main components of gastro-oesophageal reflux and tumour promoters, up-regulate MUC4 expression [Mariette, Perrais, Leteurtre, Jonckheere, Hemon, Pigny, Batra, Aubert, Triboulet and Van Seuningen (2004) Biochem. J. 377, 701–708]. HNF (hepatocyte nuclear factor) 1α and HNF4α transcription factors are known to mediate bile acid effects, and we previously identified cis-elements for these factors in MUC4 distal promoter. Our aim was to demonstrate that these two transcription factors were directly involved in MUC4 activation by bile acids. MUC4, HNF1α and HNF4α expressions were evaluated by immunohistochemistry in human oesophageal tissues. Our results indicate that MUC4, HNF1α and HNF4α were co-expressed in oesophageal metaplastic and adenocarcinomatous tissues. Studies at the mRNA, promoter and protein levels indicated that HNF1α regulates endogenous MUC4 expression by binding to two cognate cis-elements respectively located at −3332/−3327 and −3040/−3028 in the distal promoter. We also showed by siRNA (small interfering RNA) approach, co-transfection and site-directed mutagenesis that HNF1α mediates taurodeoxycholic and taurochenodeoxycholic bile acid activation of endogenous MUC4 expression and transcription in a dose-dependent manner. In conclusion, these results describe a new mechanism of regulation of MUC4 expression by bile acids, in which HNF1α is a key mediator. These results bring new insights into MUC4 up-regulation in oesophageal carcinoma associated with bile reflux.

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.

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