Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis

Saleh, Mohamed Bou; Louvet, Alexandre; Ntandja-Wandji, Line Carolle; Boleslawski, Emmanuel; Gnemmi, Viviane; Lassailly, Guillaume; Truant, Stéphanie; Maggiotto, François; Ningarhari, Massih; Artru, Florent; Anglo, Emilie; Sancho‐Bru, Pau; Corlu, Anne; Argemí, Josepmaria; Dubois-Chevalier, Julie; Dharancy, Sébastien; Eeckhoute, Jérôme; Bataller, Ramón; Maury, Philippe; Dubuquoy, Laurent

doi:10.1016/j.jhep.2021.05.041

Cited by 48 publications

(44 citation statements)

References 34 publications

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“…Activation of the CDK4/6 pathway in mouse and human iCCA suggests that combined targeting with anti-CDK4/6 inhibitors could be an effective treatment strategy. Notably, the HIPPO/YAP pathway is severely dysregulated in alcoholic hepatitis (AH), with uncontrolled activation of YAP leading to hepatocyte transdifferentiation to the biliary phenotype and the loss of hepatocyte identity with impaired regeneration ( 87 ). Using animal models, experimental cells, and human samples of AH and alcoholic cirrhosis, investigators conjunctively found that the reversal of hepatocyte defects mediated by YAP inhibition appears to be a therapeutic strategy for AH regenerative treatment.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk Among YAP, LncRNA, and Tumor-Associated Macrophages in Tumorigenesis Development

Liu

Zhang

et al. 2022

Front. Oncol.

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Long non-coding RNAs (ncRNAs), which do not encode proteins, regulate cell proliferation, tumor angiogenesis, and metastasis and are closely associated with the development, progression, and metastasis of many cancers. Tumor-associated macrophages (TAMs) in the tumor microenvironment play an important role in cancer progression. The Hippo signaling pathway regulates cell proliferation and apoptosis, maintains tissue and organ size, and homeostasis of the internal environment of organisms. Abnormal expression of Yes-associated protein (YAP), the Hippo signaling pathway key component, is widely observed in various malignancies. Further, TAM, lncRNA, and YAP are currently valuable targets for cancer immunotherapy. In this review, we have logically summarized recent studies, clarified the close association between the three factors and tumorigenesis, and analyzed the outlook of tumor immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Crosstalk Among YAP, LncRNA, and Tumor-Associated Macrophages in Tumorigenesis Development

Liu

Zhang

et al. 2022

Front. Oncol.

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“…Genome wide analysis of "bulk" RNA expression in the liver from patients with severe alcoholic hepatitis has shown features of hepatocyte senescence and marked downregulation of genes involved in mitotic cell cycle [25]. In alcoholic hepatitis, certain "surviving" hepatocytes do not proliferate but lose their identity as they transdifferentiate into cholangiocytes [24,26]. The lack of hepatocyte regeneration and the loss of hepatocyte identity are caused by the hepatocyte overexpression of Yes-associated protein [26](YAP, a transcription coactivator involved in the Hippo pathway [27]).…”

Section: Defects In Hepatocyte Regenerationmentioning

confidence: 99%

“…In alcoholic hepatitis, certain "surviving" hepatocytes do not proliferate but lose their identity as they transdifferentiate into cholangiocytes [24,26]. The lack of hepatocyte regeneration and the loss of hepatocyte identity are caused by the hepatocyte overexpression of Yes-associated protein [26](YAP, a transcription coactivator involved in the Hippo pathway [27]). Therefore, in alcoholic hepatitis, increased hepatocyte death, defective hepatocyte regeneration and hepatocyte transdifferentiation into cholangiocytes, all contribute to hepatocellular dysfunction/failure in alcoholic hepatitis.…”

Section: Defects In Hepatocyte Regenerationmentioning

confidence: 99%

Severe alcoholic hepatitis as precipitant for organ failure and ACLF

et al. 2022

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Alcoholic hepatitis is the acute deterioration of alcoholic liver disease with rapid onset or worsening of jaundice, which in severe cases, may transition to acute-on-chronic liver failure with extremely high short-term mortality, increasing with the number and severity of hepatic and extra-hepatic organ dysfunction. Diagnosis and treatment are insufficient and challenging, especially due to the complex, multi-factorial and as yet not fully understood pathogenesis. While current management is limited to steroids and best supportive care, debate is ongoing concerning liver transplantation for selected patients, and several novel approaches are under way with mixed results. These drawbacks in disease management together with increasing prevalence in Germany, and generally in Western countries, constitute an unmet need for the healthcare systems. This review tries to summarize the current status of these aspects and provides an overview for pathogenesis, management and potential future treatments.

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“…Moreover, YAP can integrate metabolic and nutrient‐sensing pathways leading to coordination of nutrient availability with the genetic program that sustains cell proliferation 15,16 . Emerging evidence has shown YAP dysregulation in alcoholic hepatitis 17 . Hence, we examined expression patterns of this transcriptional regulator in human livers from patients with alcoholism, and in murine livers that were damaged after chronic‐plus‐single binge or moderate ethanol ingestion combined with acute intoxication by carbon tetrachloride (ethanol/CCl 4 ).…”

Section: Introductionmentioning

confidence: 99%

“…15,16 Emerging evidence has shown YAP dysregulation in alcoholic hepatitis. 17 Hence, we examined expression patterns of this transcriptional regulator in human livers from patients with alcoholism, and in murine livers that were damaged after chronic-plus-single binge or moderate ethanol ingestion combined with acute intoxication by carbon tetrachloride (ethanol/CCl 4 ). Hepatocyte-specific KO were utilized to determine the function of Yap1 gene in liver regeneration following ethanol/CCl 4 .…”

Section: Introductionmentioning

confidence: 99%

Liver regeneration and ethanol detoxification: A new link in YAP regulation of ALDH1A1 during alcohol‐related hepatocyte damage

et al. 2022

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Yes‐associated protein (YAP), a central effector in the Hippo pathway, is involved in the regulation of organ size, stem cell self‐renewal, and tissue regeneration. In this study, we observed YAP activation in patients with alcoholic steatosis, hepatitis, and cirrhosis. Accumulation of this protein in the nucleus was also observed in murine livers that were damaged after chronic‐plus‐single binge or moderate ethanol ingestion combined with carbon tetrachloride intoxication (ethanol/CCl4). To understand the role of this transcriptional coactivator in alcohol‐related liver injury, we knocked out the Yap1 gene in hepatocytes of floxed homozygotes through adeno‐associated virus (AAV8)‐mediated deletion utilizing Cre recombinase. Yap1 hepatocyte‐specific knockouts (KO) exhibited hemorrhage, massive hepatic necrosis, enhanced oxidative stress, elevated hypoxia, and extensive infiltration of CD11b+ inflammatory cells into hepatic microenvironments rich for connective tissue growth factor (Ctgf) during ethanol/CCl4‐induced liver damage. Analysis of whole‐genome transcriptomics indicated upregulation of genes involved in hypoxia and extracellular matrix (ECM) remodeling, whereas genes related to hepatocyte proliferation, progenitor cell activation, and ethanol detoxification were downregulated in the damaged livers of Yap1 KO. Acetaldehyde dehydrogenase (Aldh)1a1, a gene that encodes a detoxification enzyme for aldehyde substrates, was identified as a potential YAP target because this gene could be transcriptionally activated by a hyperactive YAP mutant. The ectopic expression of the human ALDH1A1 gene caused increase in hepatocyte proliferation and decrease in hepatic necrosis, oxidative stress, ECM remodeling, and inflammation during ethanol/CCl4‐induced liver damage. Taken together, these observations indicated that YAP was crucial for liver repair during alcohol‐associated injury. Its regulation of ALDH1A1 represents a new link in liver regeneration and detoxification.

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Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis

Cited by 48 publications

References 34 publications

Crosstalk Among YAP, LncRNA, and Tumor-Associated Macrophages in Tumorigenesis Development

Crosstalk Among YAP, LncRNA, and Tumor-Associated Macrophages in Tumorigenesis Development

Severe alcoholic hepatitis as precipitant for organ failure and ACLF

Liver regeneration and ethanol detoxification: A new link in YAP regulation of ALDH1A1 during alcohol‐related hepatocyte damage

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