Molecular characterization of chronic liver disease dynamics: From liver fibrosis to acute-on-chronic liver failure

Graupera, Isabel; Isus, Laura; Coll, Mar; Pose, Elisa; Díaz, Alba; Vallverdú, Julia; Rubio-Tomás, Teresa; Martínez-Sánchez, Celia; Huelín, Patrícia; Llopis, Marta; Solé, Cristina; Fondevila, Constantino; Lozano, Juan José; Sancho‐Bru, Pau; Ginès, Pere; Aloy, Patrick

doi:10.1016/j.jhepr.2022.100482

Cited by 18 publications

(16 citation statements)

References 38 publications

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“…Also, pharmacological intervention in dHSCs and in a mouse model of liver fibrosis and extrahepatic fibrotic models show that activation of RORA prevents pericyte activation and fibrosis. In agreement with these results, human data from a cohort of chronic liver disease patients 28 showed that the reduction of RORA is associated with the progression of fibrosis. Altogether, these results indicate that RORA has a dual role in HSC physiology, playing a role in HSCs differentiation and maturation but also preventing their activation, thus suppressing its fibrogenic response.…”

Section: Discussionsupporting

confidence: 80%

“…In addition, HSCs isolated from cirrhotic patients showed lower RORA expression than quiescent HSCs (FC=-1,88, p-value=0,02) (Figure 7C), according to our data showing RORA loss during HSCs activation. Next, we evaluated the correlation of RORA gene expression with fibrosis in a cohort of patients with different stages of chronic liver disease 25 . RORA gene expression was decreased in patients with Metavir F1-4 (Figure 7D) and correlated with the FIB4 fibrosis score (Figure 7E).…”

Section: Rora Gene Expression Correlates Negatively With Human Liver ...mentioning

confidence: 99%

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Trajectory Analysis of Hepatic Stellate Cell Differentiation Reveals Metabolic Regulation of Cell Commitment and Fibrosis

Martínez García de la Torre,

Vallverdú,

et al. 2024

Preprint

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Defining the trajectory of cells during differentiation and disease offers the possibility to understand the mechanisms driving cell fate and identity. However, trajectories of human cells are largely unexplored. By investigating the proteome trajectory of iPSCs differentiation to hepatic stellate cells (dHSCs), we identified RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for HSCs commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we showed that RORA is required for mesoderm differentiation and prevents dHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice had enhanced fibrosis, RORA agonists rescued multi- organ fibrosis in in vivo models. RORA expression was consistently found to be negatively correlated with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, crucial for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease mechanisms.

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Section: Discussionsupporting

confidence: 80%

Section: Rora Gene Expression Correlates Negatively With Human Liver ...mentioning

confidence: 99%

Trajectory Analysis of Hepatic Stellate Cell Differentiation Reveals Metabolic Regulation of Cell Commitment and Fibrosis

Martínez García de la Torre,

Vallverdú,

et al. 2024

Preprint

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“…Recent studies leveraging advancements in omics approaches, have provided a more comprehensive understanding of the pathophysiological mechanisms underlying ACLF and the distinctions between patients with ACLF and those experiencing AD 10–15 . This exploration encompasses multiple dimensions of complex interactions, including lipid and amino acid metabolism, inflammation, and mitochondrial function.…”

Section: Differences In Acute‐on‐chronic Liver Failure Versus Acute D...mentioning

confidence: 99%

Acute decompensation of cirrhosis versus acute‐on‐chronic liver failure: What are the clinical implications?

Xu,

Chen,

Artru

2024

UEG Journal

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It is essential to identify the subgroup of patients who experience poorer outcomes in order to adapt clinical management effectively. In the context of liver disease, the earlier the identification occurs, the greater the range of therapeutic options that can be offered to patients. In the past, patients with acute decompensation (AD) of chronic liver disease were treated as a homogeneous group, with emphasis on identifying those at the highest risk of death. In the last 15 years, a differentiation has emerged between acute‐on‐chronic liver failure syndrome (ACLF) and AD, primarily due to indications that the latter is linked to a less favorable short‐term prognosis. Nevertheless, the definition of ACLF varies among the different knowledge societies, making it challenging to assess its true impact compared with AD. Therefore, the purpose of this review is to provide a detailed analysis emphasizing the critical importance of identifying ACLF in the field of advanced liver disease. We will discuss the differences between Eastern and Western approaches, particularly in relation to the occurrence of liver failure and disease onset. Common characteristics, such as the dynamic nature of the disease course, will be highlighted. Finally, we will focus on two key clinical implications arising from these considerations: the prevention of ACLF before its onset and the clinical management strategies once it develops, including liver transplantation and withdrawal of care.

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“…We downloaded the GSE139602 dataset derived on the GPL13667 platform (Affymetrix Human Genome U219 Array). In this database, transcriptome analysis of liver biopsies from patients at different liver disease stages, including 5 fibrosis patients, 8 compensated cirrhosis patients, 12 decompensated cirrhosis patients, 8 ACLF patients, and 6 control healthy individuals, was performed [7]. The data from the 8 ACLF patients and 6 control healthy individuals were selected for further analysis.…”

Section: Screening Of Microarray Datamentioning

confidence: 99%

Identification of potential ferroptosis hub genes in acute-on-chronic liver failure based on bioinformatics analysis and experimental verification

et al. 2023

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Background Ferroptosis plays an important role in the development of acute-on-chronic liver failure (ACLF). The present project aimed to identify and validate the potential ferroptosis-related genes in ACLF by bioinformatics analysis and experimental verification. Materials and methods The GSE139602 dataset was obtained from the Gene Expression Omnibus database and intersected with ferroptosis genes. Ferroptosis-related differentially expressed genes (DEGs) between the ACLF tissue and healthy group were analyzed using bioinformatics methods. Analysis of enrichment, protein‒protein interactions, and hub genes was conducted. Potential drugs targeting these hub genes were retrieved from the DrugBank database. Finally, we performed real-time quantitative PCR (RT-qPCR) to validate the expression of the hub genes. Results A total of 35 ferroptosis-related DEGs were screened, which were enriched in the biosynthesis of amino acids, peroxisomes, fluid shear stress and atherosclerosis. PPI network analysis indicated five ferroptosis-related hub genes, namely, HRAS, TXNRD1, NQO1, PSAT1, and SQSTM1. The experimental validation indicated that the expression levels of HRAS, TXNRD1, NQO1, and SQSTM1 were lower, while the expression level of PSAT1 was higher in ACLF model rats than in healthy rats. Conclusions Our findings reveal that PSAT1, TXNRD1, HRAS, SQSTM1 and NQO1 may affect the development of ACLF by regulating ferroptotic events. These results provide a valid reference for potential mechanisms and identification in ACLF.

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Molecular characterization of chronic liver disease dynamics: From liver fibrosis to acute-on-chronic liver failure

Cited by 18 publications

References 38 publications

Trajectory Analysis of Hepatic Stellate Cell Differentiation Reveals Metabolic Regulation of Cell Commitment and Fibrosis

Trajectory Analysis of Hepatic Stellate Cell Differentiation Reveals Metabolic Regulation of Cell Commitment and Fibrosis

Acute decompensation of cirrhosis versus acute‐on‐chronic liver failure: What are the clinical implications?

Identification of potential ferroptosis hub genes in acute-on-chronic liver failure based on bioinformatics analysis and experimental verification

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