Convergence of Wnt Signaling on the HNF4α-Driven Transcription in Controlling Liver Zonation

Colletti, Marta; Cicchini, Carla; Conigliaro, Alice; Santangelo, Laura; Alonzi, Tonino; Pasquini, Emiliano; Tripodi, Marco; Amicone, Laura

doi:10.1053/j.gastro.2009.05.038

Cited by 120 publications

(123 citation statements)

References 27 publications

(37 reference statements)

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“…However, using a human primary hepatocyte culture system that allows efficient infection with intact HCV virions [15] , and by blocking C/EBPβ Thr266 phosphorylation with a designed inhibitory dominant negative peptide [7] , we were able to demonstrate a causal effect of C/EBPβ Thr266 phosphorylation on hepatocyte proliferation and the zone-3 phenotype [14] . As previously reported [10][11][12] , we found that both β-Catenin and HIF-1α were expressed in a small acinar zone-3 in the liver from healthy controls (Figure 2A). We have determined that HCV infections expand the expression of β-Catenin and HIF-1α in non-cirrhotic livers and to a larger degree in cirrhotic livers (Figures 2A and 2B).…”

Section: Discussionsupporting

confidence: 68%

“…APC and β-Catenin modulate the liver acinar zonation and HIF-1α is induced by hypoxia [10][11][12] . Therefore, we analyzed whether HCV infection affects the expression of β-Catenin in zone-3 and whether the HCV infection affects the predictable expression of HIF-1α in the hypoxic acinar zone-3 [10][11][12] . We found that both β-Catenin and HIF-1α were expressed in a small acinar zone-3 in the liver from healthy controls (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…hepatocytes are characterized by the expression of Glutamine Synthetase (GS), β-Catenin and Hypoxia-Inducible Factor (HIF)-1 [9][10][11][12] . Expression of the GS gene in liver acinar zone-3 hepatocytes is stimulated by C/EBPβ [13] .…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis C Virus Infection in Patients is Associated With C/ EBPβ-Thr266 Phosphorylation and Hepatocyte Proliferation

Traykova

Chojkier

Buck

2016

Journal of Gastroenterology and Hepatology Research

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RESULTS:In patients with HCV infection, the HCV Core protein was preferentially co-localized with hepatocytes expressing Glutamine synthetase, phosphorylated C/EBPβ-Thr266, HIF-1α and β-Catenin. As expected, phosphorylated C/EBPβ-Thr266 was associated with hepatocyte proliferation in these patients. HCV infection markedly increased hepatocyte proliferation. CONCLUSION: This study demonstrates that HCV infection is preferentially localized to an expanded acinar zone expressing GS, where enhanced hepatocyte proliferation occurs in association with phosphorylated C/EBPβ-Thr266. A better understanding of the mechanisms of HCV infection may facilitate additional studies and potential therapeutic interventions. ABSTRACT AIM: Hepatitis C virus (HCV) infection in patients induces hepatocyte proliferation and also hepatocellular carcinoma. The mechanisms and the liver acinar distribution of the HCV infection remain unclear. The aim of this study was to determine the liver acinar localization of the infectious HCV and whether HCV infection is associated with the expression of proteins known to modulate hepatocyte proliferation. METHODS: We analyzed normal (n = 6), HCV genotype 1-infected non cirrhotic (n = 6) and HCV genotype 1-infected cirrhotic liver samples (n = 6). We performed immunofluorescent studies using antibodies against HCV Core, Glutamine synthetase (as a marker of hepatic acinar zone-3 in normal livers); phosphorylated C/EBPβ-Thr266 (since it is required for Transforming Growth Factorα-and Hepatic Growth Factor -induced hepatocyte proliferation) and ki-67 (as an indicator of hepatocyte proliferation). Also, we analyzed by QRT-PCR a proliferation microarray to compare the expression of genes associated with cell proliferation in HCV-infected patients.

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Section: Discussionsupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

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Hepatitis C Virus Infection in Patients is Associated With C/ EBPβ-Thr266 Phosphorylation and Hepatocyte Proliferation

Traykova

Chojkier

Buck

2016

Journal of Gastroenterology and Hepatology Research

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“…Notably, RLSCs were also proved to recapitulate the hepatocyte post-differentiation patterning defined as 'zonation': their spontaneous differentiation, in fact, generates periportal hepatocytes that may be induced to switch into perivenular hepatocytes by means of the convergence of Wnt signaling on the HNF4a-driven transcription. 4 Furthermore, we identified a simple cross-regulatory circuitry between HNF4a (master regulator of hepatocyte differentiation) and Snail (master regulator of the epithelial-to-mesenchymal transition, EMT), whose expression is mutually exclusive because of their direct reciprocal transcriptional repression. 2,5 These findings, relevant for the comprehension of the EMT and of the reverse process mesenchymal-to-epithelial transition (MET), have been demonstrated pivotal also for the maintenance of a stable epithelial phenotype.…”

mentioning

confidence: 99%

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

et al. 2011

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Preservation of the epithelial state involves the stable repression of epithelial-to-mesenchymal transition program, whereas maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular minicircuitry between master elements of these biological processes might provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4a, directly represses the expression of the epithelial microRNAs (miRs)-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4a, previously identified as a transcriptional repressor of Cellular differentiation implies an orchestrated sequence of events guiding stem cells/precursors toward specialized cell types based on the contemporary and strictly correlated phenomena of loss of stemness and acquisition of histotypic markers and functions. The homeostasis of the stem cell compartment requires mechanisms actively counteracting differentiation; 1 similarly, the maintenance of the differentiated state involves a stable repression of elements capable to induce morphological transition and dedifferentiation. 2 The observation that a number of stem cells are restricted to a specific differentiation fate suggests that elements pivotal for the coordinated execution of the opposite processes could be tissue-specific. Considering that stem cell compartments are rare and give rise to a heterogeneous cellular population capable to reversibly shift among different states, 3 the availability of a stable stem cell line executing specific differentiation programs discloses an unique possibility to investigate mechanisms regulating alternative cellular choices. A simple and direct molecular mini-circuitry of master elements of mutually exclusive biological processes, also able to reciprocally influence their own expression, may provide the theoretically best device to trigger such complex phenomena.We previously characterized a number of stable liver stem cell lines named RLSCs (from resident liver stem cells) that spontaneously acquire an epithelial morphology and differentiate into hepatocytes (named RLSCdH from RLSC-derived hepatocytes). Notably, RLSCs were also proved to recapitulate the hepatocyte post-differentiation patterning defined as 'zonation': their spontaneous differentiation, in fact, generates periportal hepatocytes that may be induced to switch into perivenular hepatocytes by means of the convergence of Wnt signaling on the HNF4a-driven transcription. 4 Furthermore, we identified a simple cross-regulatory circuitry between HNF4a (master regulator of hepatocyte differentiation) and Snail (master regulator of the epithelial-to-mesenchymal transition, EMT), whose expression is mutually exclusive because of their direct reciprocal transcriptional repression. 2,5 These findings, relevant for the comprehension of the EMT and of the reverse process mesenchymal-...

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“…In adult healthy hepatocytes, β-catenin is ubiquitously expressed, but it is more active in pericentral compared to periportal hepatocytes (44). Expression of β-catenin in periportal regions is inhibited by hepatocyte nuclear factor 4α (46). In contrast, pericentral hepatocytes display basal activation of β-catenin signalling, controlling expression levels of glutamine synthetase, ornithine aminotransferase and the glutamate transporter GLT-1, which together regulate glutamine metabolism (47).…”

Section: Wnt/β-catenin Signalling In Liver Metabolismmentioning

confidence: 99%

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

Shirolkar¹,

Pasic²,

Gogoi-Tiwari³

et al. 2018

jrenhep

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Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their signalling to fibrosis-driving hepatic stellate cells. The Wnt/β-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/β-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis.

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Convergence of Wnt Signaling on the HNF4α-Driven Transcription in Controlling Liver Zonation

Abstract: Our data show a direct and hitherto unknown convergence of the canonical Wnt signaling on the HNF4alpha-driven transcription providing evidences of a mechanism controlling liver zonated gene expression.

Cited by 120 publications

References 27 publications

Hepatitis C Virus Infection in Patients is Associated With C/ EBPβ-Thr266 Phosphorylation and Hepatocyte Proliferation

Hepatitis C Virus Infection in Patients is Associated With C/ EBPβ-Thr266 Phosphorylation and Hepatocyte Proliferation

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

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