scholarly journals Hepatic NF-kB-inducing Kinase (NIK) Suppresses Liver Regeneration in Chronic Liver Disease

2017 ◽  
Author(s):  
Yi Xiong ◽  
Adriana Souza Torsoni ◽  
Feihua Wu ◽  
Hong Shen ◽  
Yan Liu ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Regeneration ◽  
Chronic Liver Disease ◽  
Disease Progression ◽  
Cell Cycle Progression ◽  
Metabolic Stress ◽  
Chronic Liver ◽  
Hepatocyte Proliferation ◽  
Stat3 Pathway ◽  
Liver Disease Progression

SummaryHepatocyte replication maintains liver homeostasis and integrity. It is impaired in chronic liver disease, promoting disease progression. Herein, we have identified NF-kB-inducing kinase (NIK) as an unrecognized suppressor of hepatocyte replication. Hepatic NIK was aberrantly activated in chronic liver disease. Hepatocyte-specific deletion of NIK or its downstream mediator IKKα substantially accelerated hepatocyte proliferation and liver regeneration following partial hepatectomy. Mechanistically, NIK and IKKα suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting hepatocyte cell cycle progression. Remarkably, inactivation of hepatic NIK largely reversed suppression of the hepatic JAK2/STAT3 pathway, hepatocyte replication, and liver regeneration induced by either chronic liver injury or metabolic stress. Our data suggest that hepatic NIK acts as a rheostat for liver regeneration to restrain liver overgrowth. Pathologic activation of hepatic NIK blocks hepatocyte replication, likely contributing to liver disease progression.

scholarly journals Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yi Xiong ◽  
Adriana Souza Torsoni ◽  
Feihua Wu ◽  
Hong Shen ◽  
Yan Liu ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Regeneration ◽  
Chronic Liver Disease ◽  
Disease Progression ◽  
Partial Hepatectomy ◽  
Cell Cycle Progression ◽  
Underlying Mechanism ◽  
Chronic Liver ◽  
Hepatocyte Proliferation ◽  
Liver Disease Progression

Reparative hepatocyte replication is impaired in chronic liver disease, contributing to disease progression; however, the underlying mechanism remains elusive. Here, we identify Map3k14 (also known as NIK) and its substrate Chuk (also called IKKα) as unrecognized suppressors of hepatocyte replication. Chronic liver disease is associated with aberrant activation of hepatic NIK pathways. We found that hepatocyte-specific deletion of Map3k14 or Chuk substantially accelerated mouse hepatocyte proliferation and liver regeneration following partial-hepatectomy. Hepatotoxin treatment or high fat diet feeding inhibited the ability of partial-hepatectomy to stimulate hepatocyte replication; remarkably, inactivation of hepatic NIK markedly increased reparative hepatocyte proliferation under these liver disease conditions. Mechanistically, NIK and IKKα suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting cell cycle progression. Our data suggest that hepatic NIK and IKKα act as rheostats for liver regeneration by restraining overgrowth. Pathological activation of hepatic NIK or IKKα likely blocks hepatocyte replication, contributing to liver disease progression.

scholarly journals Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into Hepatocytes via sox9b Repression in Zebrafish

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jacquelyn O. Russell ◽  
Sungjin Ko ◽  
Satdarshan P. Monga ◽  
Donghun Shin
Keyword(s):  
Liver Disease ◽  
Liver Regeneration ◽  
Notch Signaling ◽  
Chronic Liver Disease ◽  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Chronic Liver ◽  
Hepatocyte Proliferation ◽  
Hepatocyte Differentiation

Liver regeneration after most forms of injury is mediated through the proliferation of hepatocytes. However, when hepatocyte proliferation is impaired, such as during chronic liver disease, liver progenitor cells (LPCs) arising from the biliary epithelial cell (BEC) compartment can give rise to hepatocytes to mediate hepatic repair. Promotion of LPC-to-hepatocyte differentiation in patients with chronic liver disease could serve as a potentially new therapeutic option, but first requires the identification of the molecular mechanisms driving this process. Notch signaling has been identified as an important signaling pathway promoting the BEC fate during development and has also been implicated in regulating LPC differentiation during regeneration. SRY-related HMG box transcription factor 9 (Sox9) is a direct target of Notch signaling in the liver, and Sox9 has also been shown to promote the BEC fate during development. We have recently shown in a zebrafish model of LPC-driven liver regeneration that inhibition of Hdac1 activity through MS-275 treatment enhances sox9b expression in LPCs and impairs LPC-to-hepatocyte differentiation. Therefore, we hypothesized that inhibition of Notch signaling would promote LPC-to-hepatocyte differentiation by repressing sox9b expression in zebrafish. We ablated the hepatocytes of Tg(fabp10a:CFP-NTR) larvae and blocked Notch activation during liver regeneration through treatment with γ-secretase inhibitor LY411575 and demonstrated enhanced induction of Hnf4a in LPCs. Alternatively, enhancing Notch signaling via Notch3 intracellular domain (N3ICD) overexpression impaired Hnf4a induction. Hepatocyte ablation in sox9b heterozygous mutant embryos enhanced Hnf4a induction, while BEC-specific Sox9b overexpression impaired LPC-to-hepatocyte differentiation. Our results establish the Notch-Sox9b signaling axis as inhibitory to LPC-to-hepatocyte differentiation in a well-established in vivo LPC-driven liver regeneration model.

1129 SERPIN-B3 AS A PRO-FIBROGENIC MEDIATOR CONTRIBUTING TO CHRONIC LIVER DISEASE PROGRESSION

2013 ◽  
Vol 58 ◽  
pp. S460
Author(s):  
C. Paternostro ◽  
C. Busletta ◽  
C. Turato ◽  
S. Cannito ◽  
G. Villano ◽  
...  
Keyword(s):  
Liver Disease ◽  
Chronic Liver Disease ◽  
Disease Progression ◽  
Chronic Liver ◽  
Liver Disease Progression

OC-03 SERPIN-B3 as a pro-fibrogenic mediator contributing to chronic liver disease progression

2013 ◽  
Vol 45 ◽  
pp. S2
Author(s):  
C. Paternostro ◽  
C. Busletta ◽  
C. Turato ◽  
S. Cannito ◽  
A. Biasiolo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Chronic Liver Disease ◽  
Disease Progression ◽  
Chronic Liver ◽  
Liver Disease Progression

scholarly journals The gut microbiome and hepatocellular carcinoma: Implications for early diagnostic biomarkers and novel therapies

Liver Cancer ◽  
2021 ◽  
Author(s):  
Yongbo Kang ◽  
Yue Cai ◽  
Ying Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Gut Microbiota ◽  
Chronic Liver Disease ◽  
Disease Progression ◽  
Chronic Liver ◽  
Therapeutic Modalities ◽  
Liver Disease Progression ◽  
Gut Microbe ◽  
Early Diagnostic

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. HCC almost exclusively develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation and regeneration that typically spans decades. Recently, increasing investigation of the microbiome–gut–liver axis enhances our understanding of the role of the gut microbiota in promoting the progression of liver disease and the development of HCC. In this review, we summarize mechanisms by which the gut microbiota promotes hepatocarcinogenesis, focusing on bacterial dysbiosis, the leaky gut, microbe-associated molecular patterns and bacterial metabolites as key pathways that drive cancer-promoting liver inflammation, fibrosis and genotoxicity. Furthermore, we discuss the important potential of gut microbiota as an early diagnostic biomarker of HCC. Gut microbiota may be as a promising target for the simultaneous prevention of chronic liver disease progression and HCC development in patients with advanced liver disease. We outlook in detail therapeutic modalities in which targeting the gut microbiota for the prevention of disease progression and HCC development seems promising.

scholarly journals Oral Methylthioadenosine Administration Attenuates Fibrosis and Chronic Liver Disease Progression in Mdr2−/− Mice

PLoS ONE ◽  
2010 ◽  
Vol 5 (12) ◽  
pp. e15690 ◽  
Author(s):  
M. Ujue Latasa ◽  
Carmen Gil-Puig ◽  
Maite G. Fernández-Barrena ◽  
Carlos M. Rodríguez-Ortigosa ◽  
Jesús M. Banales ◽  
...  
Keyword(s):  
Liver Disease ◽  
Chronic Liver Disease ◽  
Disease Progression ◽  
Chronic Liver ◽  
Liver Disease Progression
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