scholarly journals Modulation of hepatic mRNA-miRNA panel linked to NAFLD/NASH Hippo signaling and gut microbiota after administration of kefir in Non-Alcoholic Steatohepatitis Rat Model

2021 ◽  
Author(s):  
Noha Salah ◽  
Amal Mansour ◽  
Nagwa M Abo El Magd ◽  
Amany Helmy Hasanin ◽  
Mohamed Kamel Hassan ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Effector Proteins ◽  
Hippo Signaling ◽  
Subsequent Increase ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Lipid Panel ◽  
Epigenetic Regulator ◽  
High Sucrose ◽  
Tgf Β1

Abstract Non-alcoholic steatohepatitis (NASH) is the clinically aggressive variant of non-alcoholic fatty liver disease. Hippo pathway dysregulation can contribute to NASH development and progression. The use of probiotics is effective in NASH management. Our aim is to investigate the efficacy of kefir Milk in NASH management via modulation of hepatic mRNA-miRNA based panel linked to NAFLD/NASH Hippo signaling and gut microbita regulated genes which was identified using bioinformatics tools. Firstly, we analyzed mRNAs (SOX11, SMAD4 and AMOTL2), and their epigenetic regulator (miR-6807) followed by validation of target effector proteins (TGFB1, IL6 and HepPar1). Molecular, biochemical, and histopathological, analyses were used to evaluate the effects of kefir on high sucrose high fat (HSHF) diet -induced NASH in rats. We found that administration of Kefir proved to prevent steatosis and development of the inflammatory component of NASH. Moreover, Kefir improved liver function and lipid panel. At the molecular level, kefir down-regulated the expression of miR 6807-5p with subsequent increase in the expression of SOX 11, AMOTL2 associated with downregulated SMAD4, resulting in reduction in the expression of the inflammatory and fibrotic markers, IL6 and TGF-β1 in the treated and prophylactic groups compared to the untreated rats. In conclusion, Kefir suppressed NASH progression and improved both fibrosis and hepatic inflammation. The produced effect was correlated with modulation of SOX11, SMAD4 and AMOTL2 mRNAs) – (miR-6807-5p) – (TGFB, IL6 and, HepPar1) expression.

scholarly journals Signaling in Simple Steatosis and Non-alcoholic Steatohepatitis Cirrhosis: TGF-β1, YAP/TAZ, and Hedgehog Pathway Activity

2018 ◽  
Vol 6 (2) ◽  
pp. 26-30
Author(s):  
Sina Mohagheghi ◽  
Zohreh Khajehahmadi ◽  
Heidar Tavilani
Keyword(s):  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Alcoholic Fatty Liver ◽  
Simple Steatosis ◽  
Alcoholic Steatohepatitis ◽  
Alcoholic Fatty Liver Disease ◽  
Tgf Β1

Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of fat in the liver tissue that is usually associated with metabolic disorders. Traditionally, the disease is regarded as a spectrum of pathological conditions ranging from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH) and hepatic fibrosis with progression to cirrhosis. However, so far, there is no available explanation for the disease progression. Several signaling pathways such as transforming growth factor (TGF)-β, hedgehog (HH), and yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling are attributed to the NAFLD pathogenesis. TGF-β1 pathway component expression aligns with HH pathway ligands expression elevate in NASH cirrhosis while they decrease in SS. YAP and TAZ are two transcriptional co-activators from the Hippo signaling pathway. Similarly, the TAZ level (but not YAP1) is higher in NASH cirrhosis compared to SS. In addition, these three signaling pathways have little molecular similarity but their changes are totally similar in SS and NASH cirrhosis. The present review discusses the main changes in the expression of TGF-β, HH, and YAP/TAZ pathway components in SS and NASH cirrhosis. It is hoped that these data provide a better understanding of the mechanisms that underlie the pathophysiology of NAFLD.

scholarly journals Loss of Anks6 leads to YAP deficiency and liver abnormalities

2020 ◽  
Vol 29 (18) ◽  
pp. 3064-3080
Author(s):  
Merlin Airik ◽  
Markus Schüler ◽  
Blake McCourt ◽  
Anna-Carina Weiss ◽  
Nathan Herdman ◽  
...  
Keyword(s):  
Bile Duct ◽  
Transcriptional Activity ◽  
Hippo Pathway ◽  
Renal Cysts ◽  
Effector Proteins ◽  
Hippo Signaling ◽  
Knockout Mouse Model ◽  
Developmental Abnormalities ◽  
Ductal Plate ◽  
Biochemical Analyses

Abstract ANKS6 is a ciliary protein that localizes to the proximal compartment of the primary cilium, where it regulates signaling. Mutations in the ANKS6 gene cause multiorgan ciliopathies in humans, which include laterality defects of the visceral organs, renal cysts as part of nephronophthisis and congenital hepatic fibrosis (CHF) in the liver. Although CHF together with liver ductal plate malformations are common features of several human ciliopathy syndromes, including nephronophthisis-related ciliopathies, the mechanism by which mutations in ciliary genes lead to bile duct developmental abnormalities is not understood. Here, we generated a knockout mouse model of Anks6 and show that ANKS6 function is required for bile duct morphogenesis and cholangiocyte differentiation. The loss of Anks6 causes ciliary abnormalities, ductal plate remodeling defects and periportal fibrosis in the liver. Our expression studies and biochemical analyses show that biliary abnormalities in Anks6-deficient livers result from the dysregulation of YAP transcriptional activity in the bile duct-lining epithelial cells. Mechanistically, our studies suggest, that ANKS6 antagonizes Hippo signaling in the liver during bile duct development by binding to Hippo pathway effector proteins YAP1, TAZ and TEAD4 and promoting their transcriptional activity. Together, this study reveals a novel function for ANKS6 in regulating Hippo signaling during organogenesis and provides mechanistic insights into the regulatory network controlling bile duct differentiation and morphogenesis during liver development.

scholarly journals Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

2017 ◽  
Vol 114 (18) ◽  
pp. 4691-4696 ◽  
Author(s):  
Youngeun Kim ◽  
Wantae Kim ◽  
Yonghee Song ◽  
Jeong-Rae Kim ◽  
Kyungjoo Cho ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Dependent Manner ◽  
Subsequent Increase ◽  
Biological Responses ◽  
Expression Of Genes ◽  
Core Components ◽  
The Stability ◽  
The Hippo Pathway

Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination−deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.

scholarly journals Effect of YAP/TAZ on megakaryocyte differentiation and platelet production

2020 ◽  
Vol 40 (8) ◽  
Author(s):  
Chanchao Lorthongpanich ◽  
Nittaya Jiamvoraphong ◽  
Phatchanat Klaihmon ◽  
Usaneeporn Lueangamornnara ◽  
Yaowalak U-pratya ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Genetic Manipulation ◽  
Hippo Pathway ◽  
Effector Proteins ◽  
Minor Effect ◽  
Hippo Signaling ◽  
In Vitro Production ◽  
Platelet Production

Abstract Platelet transfusion is required for life-threatening thrombocytopenic bleeding, and single donor platelet concentrate is the ideal transfusion product. However, due to the inadequate number of donors that can donate a large volume of platelets, in vitro platelets production could be an alternative. We developed an in vitro production system designed to increase the platelet production yield from cultured cells. Previously, we reported that depletion of a Hippo pathway core kinase (LATS1/2) inhibited platelet production from cultured megakaryocytes. In the present study, we further investigated the role of the Hippo pathway in megakaryocyte proliferation and platelet production by focusing on the role of its effector proteins (YAP and TAZ), which are down-stream targets of LATS1/2 kinase. We found that YAP plays an essential role in megakaryoblastic cell proliferation, maturation, and platelet production, while TAZ showed minor effect. Knockdown of YAP, either by genetic manipulation or pharmaceutical molecule, significantly increased caspase-3-mediated apoptosis in cultured megakaryocytes, and increased platelet production as opposed to overexpressing YAP. We, therefore, demonstrate a paradigm for the regulation of megakaryocyte development and platelet production via the Hippo signaling pathway, and suggest the potential use of an FDA-approved drug to induce higher platelet production in cultured cells.

Prevalence, diagnosis and treatment with 3 different statins of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in military personnel. Do genetics play a role?

2020 ◽  
Vol 18 ◽  
Author(s):  
Georgios Sfikas ◽  
Michael Psallas ◽  
Charalambos Koumaras ◽  
Konstantinos Imprialos ◽  
Evangelos Perdikakis ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Military Personnel ◽  
Fatty Liver Disease ◽  
Exercise Group ◽  
Severe Form ◽  
Laboratory Evaluation ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Alcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), are major health problems worldwide. Genetics may play a role in the pathogenesis of NAFLD/NASH. Aim: To investigate the prevalence of NAFLD/NASH in 5,400 military personnel and evaluate the effect of treatment with 3 statins on NAFLD/NASH using 2 non-invasive scores [NAFLD Activity Score (NAS); Fibrosis-4 score (FIB-4)]. Methods: During the mandatory annual medical check-up, military personnel underwent a clinical and laboratory evaluation. Participants with NAFLD/NASH were randomised to 4 groups (n=151 each): dietexercise, atorvastatin, rosuvastatin or pitavastatin for 1 year (i.e. until the next routine evaluation). Results: From all the participants, 613 had NAFLD/NASH (prevalence 11.3 vs 39.8% in the general population, p<0.001); 604 consented to participate in the study. After a year of treatment, the diet-exercise group showed no significant changes in both scores (NAS 4.98 baseline vs 5.62, p=0.07; FIB-4 3.42 vs 3.52, p=0.7). For the atorvastatin group, both scores were reduced (NAS 4.97 vs 1.95, p<0.001, FIB-4 3.56 vs 0.83, p<0.001), for rosuvastatin (NAS 5.55 vs 1.81, p<0.001, FIB-4 3.61 vs 0.79, p<0.001), and for pitavastatin (NAS 4.89 vs 1.99, p<0.001, FIB-4 3.78 vs 0.87, p<0.001). Conclusions : Atorvastatin, rosuvastatin and pitavastatin have a beneficial and safe effect in NAFLD/NASH patients as recorded by the improvement in the NAS (representing NAFLD activity) and FIB-4 (representing liver fibrosis) scores. Since both those with and without NAFLD/NASH shared several baseline characteristics, genetics may play a role in the pathogenesis of NAFLD/NASH and its treatment with statins.

scholarly journals Dual-specificity phosphatase 3 deletion promotes obesity, non-alcoholic steatohepatitis and hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sophie Jacques ◽  
Arash Arjomand ◽  
Hélène Perée ◽  
Patrick Collins ◽  
Alice Mayer ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Liver Damage ◽  
Chow Diet ◽  
Serum Triglycerides ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Dual Specificity ◽  
Dual Specificity Protein Phosphatase

AbstractNon-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic pathology in Western countries. It encompasses a spectrum of conditions ranging from simple steatosis to more severe and progressive non-alcoholic steatohepatitis (NASH) that can lead to hepatocellular carcinoma (HCC). Obesity and related metabolic syndrome are important risk factors for the development of NAFLD, NASH and HCC. DUSP3 is a small dual-specificity protein phosphatase with a poorly known physiological function. We investigated its role in metabolic syndrome manifestations and in HCC using a mouse knockout (KO) model. While aging, DUSP3-KO mice became obese, exhibited insulin resistance, NAFLD and associated liver damage. These phenotypes were exacerbated under high fat diet (HFD). In addition, DEN administration combined to HFD led to rapid HCC development in DUSP3-KO compared to wild type (WT) mice. DUSP3-KO mice had more serum triglycerides, cholesterol, AST and ALT compared to control WT mice under both regular chow diet (CD) and HFD. The level of fasting insulin was higher compared to WT mice, though, fasting glucose as well as glucose tolerance were normal. At the molecular level, HFD led to decreased expression of DUSP3 in WT mice. DUSP3 deletion was associated with increased and consistent phosphorylation of the insulin receptor (IR) and with higher activation of the downstream signaling pathway. In conclusion, our results support a new role for DUSP3 in obesity, insulin resistance, NAFLD and liver damage.

scholarly journals Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 611
Author(s):  
Kelly Coffey
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Hippo Pathway ◽  
Effector Proteins ◽  
Migration And Invasion ◽  
Cell Contact ◽  
Cellular Localisation ◽  
Kinase Cascade ◽  
The Hippo Pathway ◽  
Emergence Of Resistance

Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

scholarly journals Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 184
Author(s):  
Daryl Ramai ◽  
Waqqas Tai ◽  
Michelle Rivera ◽  
Antonio Facciorusso ◽  
Nicola Tartaglia ◽  
...  
Keyword(s):  
Public Health ◽  
Hepatocellular Carcinoma ◽  
Lipid Peroxidation ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Natural Progression ◽  
Public Health Threat ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma (HCC). The progression of NASH to HCC was initially defined according to a two-hit model which involved the development of steatosis, followed by lipid peroxidation and inflammation. However, current research defines a “multi-hit” or “multi-parallel hit” model which synthesizes several contributing pathways involved in progressive fibrosis and oncogenesis. This perspective considers the effects of cellular, genetic, immunologic, metabolic, and endocrine pathways leading up to HCC which underscores the complexity of this condition. This article will provide an updated review of the pathogenic mechanisms leading from NASH to HCC as well as an exploration of the role of biomarkers and screening.

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