Loss of liver function in chronic liver disease: An identity crisis

Berasain, Carmen; Arechederra, María; Argemí, Josepmaria; Fernández‐Barrena, Maite G.; Avila, Matı́as A.

doi:10.1016/j.jhep.2022.09.001

Cited by 40 publications

(35 citation statements)

References 163 publications

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“…Moreover, it is important to note that our results demonstrate that preventing SLU7 downregulation in damaged mouse liver cells helps to preserve the hepatocellular functions restoring hepatocellular differentiation and, importantly, protects the liver against chronic injury [ 19 ]. Therefore, these results reinforce the potential of differentiation therapies such as, for instance, HNF4α1 [ 119 , 120 ] or CBPα [ 121 , 122 ] restitution to treat liver diseases [ 29 ], presenting SLU7 as a new target.…”

Section: Slu7 In Human Diseasesupporting

confidence: 60%

“…For instance, stronger expression is detected in the brain, thyroid or testis, while lower expression is found in the pancreas or salivary glands [ 28 ]. Mouse Slu7 transcripts are abundant in the developing heart [ 21 ], but negligible in the liver where its expression increases after birth [ 15 , 29 ].…”

Section: Characterization Of Slu7mentioning

confidence: 99%

“…Alternative splicing is cell-specific and responds to environmental signals [ 42 ]. Therefore, the relative proportion of the different isoforms determines cellular identity and adaptation and varies during development, aging, physiological responses and diseased states [ 26 , 29 , 43 ]. Consequently, the dysregulation of constitutive and alternative precursor mRNA splicing processes is implicated in multiple human diseases, including cancer [ 37 , 44 ].…”

Section: Slu7 Regulates Gene Expression At Different Levelsmentioning

confidence: 99%

“…A few years ago, we demonstrated that SLU7 is essential to maintain the differentiation, the metabolic function and the quiescence of hepatocytes [ 15 , 29 ] through the different mechanisms already detailed above. Accordingly, in vivo SLU7 knockdown in mouse and in human liver cells resulted in profound changes in pre-mRNA splicing and gene expression, promoting hepatocellular de-differentiation and impairing metabolic responses [ 15 ].…”

Section: Slu7 Functionsmentioning

confidence: 99%

“…Moreover, SLU7 downregulation also induces stress-response genes such as activating transcription factor 3 ( Atf3 ) or Tp53 , increases hepatocellular proliferation and induces a metabolic switch to a tumor-like glycolytic phenotype, triggering the expression of hexokinase 2 ( Hk2 ) and pyruvate kinase m2 ( Pkm2 ) and reducing the corresponding isoforms glucokinase ( Gck ) and L-pyruvate kinase ( Lpk ) [ 15 ]. Taken together, these observations highlight the existence of a hierarchical and complex network of gene expression regulation involved in the maintenance of the adult liver phenotype, in which SLU7 plays a major role [ 29 ].…”

Section: Slu7 Functionsmentioning

confidence: 99%

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SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease

Gárate-Rascón

Recalde

Rojo

et al. 2022

IJMS

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SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3′ splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.

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Section: Slu7 In Human Diseasesupporting

confidence: 60%

Section: Characterization Of Slu7mentioning

confidence: 99%

Section: Slu7 Regulates Gene Expression At Different Levelsmentioning

confidence: 99%

Section: Slu7 Functionsmentioning

confidence: 99%

Section: Slu7 Functionsmentioning

confidence: 99%

See 3 more Smart Citations

SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease

Gárate-Rascón

Recalde

Rojo

et al. 2022

IJMS

Self Cite

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Sweet dreams could be made of this: carbohydrate‐responsive element‐binding protein (ChREBP) as a target for hepatocellular carcinoma therapy

Fernández‐Barrena,

Avila

2024

Molecular Oncology

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Rewiring of cellular metabolism is now fully recognized as a hallmark of cancer. Tumor cells reprogram metabolic pathways to meet the energetic and macromolecular demands to support unrestricted growth and survival under unfavorable conditions. It is becoming apparent that these adaptations underpin most of the traits that define a cancer cell's identity, including the ability to avoid immune surveillance, endure nutrient and oxygen restrictions, detach and migrate from their natural histological niche, and avert human‐made aggressions (i.e., therapy). In a recent study, Benichou and collaborators identify carbohydrate‐responsive element‐binding protein (ChREBP), a master regulator of physiological glucose metabolism, as an oncogene in hepatocellular carcinoma (HCC) development. Upregulation of ChREBP expression results in a self‐stimulatory loop interconnecting PI3K/AKT signaling and glucose metabolism to feed fatty acid and nucleotide synthesis supporting tumorigenesis. Importantly, pharmacological inhibition of ChREBP activity quells in vivo HCC tumor growth without causing systemic toxicity. This study identifies novel oncometabolic pathways and open up new avenues to improve the treatment of a deadly tumor.

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The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche

Gonzalez‐Sanchez,

Vaquero,

Caballero‐Diaz

et al. 2024

The Journal of Pathology

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Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro‐fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro‐inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4‐treated ΔEGFR mice when compared with CCl4‐treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro‐fibrotic and pro‐inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase‐dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Loss of liver function in chronic liver disease: An identity crisis

Cited by 40 publications

References 163 publications

SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease

SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease

Sweet dreams could be made of this: carbohydrate‐responsive element‐binding protein (ChREBP) as a target for hepatocellular carcinoma therapy

The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche

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