Hepatocyte Stress Increases Expression of Yes‐Associated Protein and Transcriptional Coactivator With PDZ‐Binding Motif in Hepatocytes to Promote Parenchymal Inflammation and Fibrosis

Mooring, Meghan; Fowl, Brendan H.; Lum, Shelly Zing Chin; Liu, Ye; Yao, Kai; Softic, Samir; Kirchner, Rory; Bernstein, Aaron; Singhi, Aatur D.; Jay, Daniel G.; Kahn, C. Ronald; Camargo, Fernando D.; Yimlamai, Dean

doi:10.1002/hep.30928

Cited by 111 publications

(127 citation statements)

References 49 publications

(64 reference statements)

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“…In human umbilical vein endothelial cells, overexpression of YAP induces expression of a set of pro-inflammatory genes, such as IL-6, VCAM1, and ICAM1 [ 45 ]. Likewise, hepatocyte-specific overexpression of YAP in mice upregulates the expression of inflammatory factors, including IL-1β and TNFα [ 46 ]. Thus, YAP may directly regulate a set of genes related to immune and inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

YAP in epithelium senses gut barrier loss to deploy defenses against pathogens

Yang

et al. 2020

PLoS Pathog

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Pathogens commonly disrupt the intestinal epithelial barrier; however, how the epithelial immune system senses the loss of intestinal barrier as a danger signal to activate selfdefense is unclear. Through an unbiased approach in the model nematode Caenorhabditis elegans, we found that the EGL-44/TEAD transcription factor and its transcriptional activator YAP-1/YAP (Yes-associated protein) were activated when the intestinal barrier was disrupted by infections with the pathogenic bacterium Pseudomonas aeruginosa PA14. Gene Ontology enrichment analysis of the genes containing the TEAD-binding sites revealed that "innate immune response" and "defense response to Gram-negative bacterium" were two top significantly overrepresented terms. Genetic inactivation of yap-1 and egl-44 significantly reduced the survival rate and promoted bacterial accumulation in worms after bacterial infections. Furthermore, we found that disturbance of the E-cadherin-based adherens junction triggered the nuclear translocation and activation of YAP-1/YAP in the gut of worms. Although YAP is a major downstream effector of the Hippo signaling, our study revealed that the activation of YAP-1/YAP was independent of the Hippo pathway during disruption of intestinal barrier. After screening 10 serine/threonine phosphatases, we identified that PP2A phosphatase was involved in the activation of YAP-1/YAP after intestinal barrier loss induced by bacterial infections. Additionally, our study demonstrated that the function of YAP was evolutionarily conserved in mice. Our study highlights how the intestinal epithelium recognizes the loss of the epithelial barrier as a danger signal to deploy defenses against pathogens, uncovering an immune surveillance program in the intestinal epithelium.

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Section: Discussionmentioning

confidence: 99%

YAP in epithelium senses gut barrier loss to deploy defenses against pathogens

Yang

et al. 2020

PLoS Pathog

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“…In mice, overexpression of hepatocyte TAZ is sufficient to drive NASH progression, whereas TAZ silencing attenuates inflammation and fibrosis ( 149 ). Hepatocyte Hippo pathway activity also upregulates expression of the pro-inflammatory and pro-fibrotic gene, Cyr61/CCN1 , which is highly expressed in livers of NASH patients ( 205 ).…”

Section: Potential Of Fibroblast Growth Factor 21 Physiology As a Thementioning

confidence: 99%

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

2020

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The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in the liver. Approximately one-sixth of the NAFLD population progresses to non-alcoholic steatohepatitis (NASH) with liver inflammation, hepatocyte injury and cell death, liver fibrosis and cirrhosis. NASH is one of the leading causes of liver transplant, and an increasingly common cause of hepatocellular carcinoma (HCC), underscoring the need for intervention. The complex pathophysiology of NASH, and a predicted prevalence of 3–5% of the adult population worldwide, has prompted drug development programs aimed at multiple targets across all stages of the disease. Currently, there are no approved therapeutics. Liver-related morbidity and mortality are highest in more advanced fibrotic NASH, which has led to an early focus on anti-fibrotic approaches to prevent progression to cirrhosis and HCC. Due to limited clinical efficacy, anti-fibrotic approaches have been superseded by mechanisms that target the underlying driver of NASH pathogenesis, namely steatosis, which drives hepatocyte injury and downstream inflammation and fibrosis. Among this wave of therapeutic mechanisms targeting the underlying pathogenesis of NASH, the hormone fibroblast growth factor 21 (FGF21) holds considerable promise; it decreases liver fat and hepatocyte injury while suppressing inflammation and fibrosis across multiple preclinical studies. In this review, we summarize preclinical and clinical data from studies with FGF21 and FGF21 analogs, in the context of the pathophysiology of NASH and underlying metabolic diseases.

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“…Evidence has been shown that YAP is a core component of the Hippo pathway, which could promote inflammation response in hepatocytes (Mooring et al 2019). Zhou et al indicated that YAP could aggravate inflammatory bowel disease via promoting M1 macrophage polarization (Zhou et al 2019a).…”

Section: Is Activated Yap Signaling In Lps-stimulated Macrophagesmentioning

confidence: 99%

Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation by regulation of β-catenin and YAP pathways

et al. 2021

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Evidence has been shown that indoxyl sulfate (IS) could impair kidney and cardiac functions. Moreover, macrophage polarization played important roles in chronic kidney disease and cardiovascular disease. IS acts as a nephron-vascular toxin, whereas its effect on macrophage polarization during inflammation is still not fully elucidated. In this study, we aimed to investigate the effect of IS on macrophage polarization during lipopolysaccharide (LPS) challenge. THP-1 monocytes were incubated with phorbol 12-myristate-13-acetate (PMA) to differentiate into macrophages, and then incubated with LPS and IS for 24 h. ELISA was used to detect the levels of TNFα, IL-6, IL-1β in THP-1-derived macrophages. Western blot assay was used to detect the levels of arginase1 and iNOS in THP-1-derived macrophages. Percentages of HLA-DR-positive cells (M1 macrophages) and CD206-positive cells (M2 macrophages) were detected by flow cytometry. IS markedly increased the production of the pro-inflammatory factors TNFα, IL-6, IL-1β in LPS-stimulated THP-1-derived macrophages. In addition, IS induced M1 macrophage polarization in response to LPS, as evidenced by the increased expression of iNOS and the increased proportion of HLA-DR+ macrophages. Moreover, IS downregulated the level of β-catenin, and upregulated the level of YAP in LPS-stimulated macrophages. Activating β-catenin signaling or inhibiting YAP signaling suppressed the IS-induced inflammatory response in LPS-stimulated macrophages by inhibiting M1 polarization. IS induced M1 macrophage polarization in LPS-stimulated macrophages via inhibiting β-catenin and activating YAP signaling. In addition, this study provided evidences that activation of β-catenin or inhibition of YAP could alleviate IS-induced inflammatory response in LPS-stimulated macrophages. This finding may contribute to the understanding of immune dysfunction observed in chronic kidney disease and cardiovascular disease.

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Hepatocyte Stress Increases Expression of Yes‐Associated Protein and Transcriptional Coactivator With PDZ‐Binding Motif in Hepatocytes to Promote Parenchymal Inflammation and Fibrosis

Cited by 111 publications

References 49 publications

YAP in epithelium senses gut barrier loss to deploy defenses against pathogens

YAP in epithelium senses gut barrier loss to deploy defenses against pathogens

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation by regulation of β-catenin and YAP pathways

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