Alcohol-associated liver disease: Epidemiology and management

Hernández-Évole, Helena; Jiménez-Esquivel, Natalia; Pose, Elisa; Bataller, Ramón

doi:10.1016/j.aohep.2023.101162

Cited by 13 publications

(6 citation statements)

References 117 publications

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“…H 2 O 2 and Galactosamine serve as experimental cell toxins, offering a comparative basis for assessing the effects of toxins not yet employed clinically. Ethanol is a well-established contributor to liver injury, particularly in cases of severe alcohol-driven liver diseases such as alcohol-related severe hepatitis [ 27 ]. Understanding ethanol's impact at the cellular level may unveil new therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Delineating the heterogeneity of senescence-induced-functional alterations in hepatocytes

Kumar,

Hassan,

Tacke

et al. 2024

Cell. Mol. Life Sci.

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Background and aim Cellular senescence of hepatocytes involves permanent cell cycle arrest, disrupted cellular bioenergetics, resistance to cell death, and the release of pro-inflammatory cytokines. This ‘zombie-like’ state perpetuates harmful effects on tissues and holds potential implications for liver disease progression. Remarkably, senescence exhibits heterogeneity, stemming from two crucial factors: the inducing stressor and the cell type. As such, our present study endeavors to characterize stressor-specific changes in senescence phenotype, its related molecular patterns, and cellular bioenergetics in primary mouse hepatocytes (PMH) and hepatocyte-derived liver organoids (HepOrgs). Methods PMH, isolated by collagenase-perfused mouse liver (C57B6/J; 18–23 weeks), were cultured overnight in William’s E-medium supplemented with 2% FBS, l-glutamine, and hepatocyte growth supplements. HepOrgs were developed by culturing cells in a 3D matrix for two weeks. The senescence was induced by DNA damage (doxorubicin, cisplatin, and etoposide), oxidative stress (H2O2, and ethanol), and telomere inhibition (BIBR-1532), p53 activation (nutlin-3a), DNA methyl transferase inhibition (5-azacitidine), and metabolism inhibitors (galactosamine and hydroxyurea). SA-β galactosidase activity, immunofluorescence, immunoblotting, and senescence-associated secretory phenotype (SASP), and cellular bioenergetics were used to assess the senescence phenotype. Results Each senescence inducer triggers a unique combination of senescence markers in hepatocytes. All senescence inducers, except hydroxyurea and ethanol, increased SA-β galactosidase activity, the most commonly used marker for cellular senescence. Among the SASP factors, CCL2 and IL-10 were consistently upregulated, while Plasminogen activator inhibitor-1 exhibited global downregulation across all modes of senescence. Notably, DNA damage response was activated by DNA damage inducers. Cell cycle markers were most significantly reduced by doxorubicin, cisplatin, and galactosamine. Additionally, DNA damage-induced senescence shifted cellular bioenergetics capacity from glycolysis to oxidative phosphorylation. In HepOrgs exposed to senescence inducers, there was a notable increase in γH2A.X, p53, and p21 levels. Interestingly, while showing a similar trend, SASP gene expression in HepOrgs was significantly higher compared to PMH, demonstrating a several-fold increase. Conclusion In our study, we demonstrated that each senescence inducer activates a unique combination of senescence markers in PMH. Doxorubicin demonstrated the highest efficacy in inducing senescence, followed by cisplatin and H2O2, with no impact on apoptosis. Each inducer prompted DNA damage response and mitochondrial dysfunction, independent of MAPK/AKT. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Delineating the heterogeneity of senescence-induced-functional alterations in hepatocytes

Kumar,

Hassan,

Tacke

et al. 2024

Cell. Mol. Life Sci.

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“…In the absence of liver-directed pharmacotherapies, complete alcohol cessation is thus the first-line and only treatment for all stages of ALD. [31,32] Notably, the presence of coexisting metabolic risk factors (obesity and diabetes) in addition to alcohol drinking confers a higher risk of developing cirrhosis. [12] Under the new SLD nomenclature, the coexistence of one metabolic risk factor (obesity or a metabolic syndrome trait) and alcohol drinking is now recognized as metabolic dysfunction and alcohol-associated liver disease (MetALD), a distinct diagnosis from ALD (which is defined and driven by harmful levels of alcohol consumption alone).…”

Section: Alcohol Usementioning

confidence: 99%

“…[4] However, whether and how intervening on metabolic risk factors may mitigate the risk of MetALD progression is a large research gap as discussed below. [32]…”

Section: Alcohol Usementioning

confidence: 99%

“…Reductions in alcohol drinking may improve outcomes; however, the data are most robust for complete abstinence. In the absence of liver-directed pharmacotherapies, complete alcohol cessation is thus the first-line and only treatment for all stages of ALD 31,32 …”

Section: Alcohol Usementioning

confidence: 99%

“…Under the new SLD nomenclature, the coexistence of one metabolic risk factor (obesity or a metabolic syndrome trait) and alcohol drinking is now recognized as metabolic dysfunction and alcohol-associated liver disease (MetALD), a distinct diagnosis from ALD (which is defined and driven by harmful levels of alcohol consumption alone) 4 . However, whether and how intervening on metabolic risk factors may mitigate the risk of MetALD progression is a large research gap as discussed below 32 …”

Section: Alcohol Usementioning

confidence: 99%

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A public health perspective on mitigating the global burden of chronic liver disease

Balakrishnan,

Rehm

2023

Hepatology

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Chronic liver disease (CLD) is a significant global health problem. Epidemiological trends do not show improvement in CLD incidence but rather a shift in etiologies, with steatotic liver disease (SLD) from metabolic dysfunction and alcohol becoming increasingly important causes. Consequently, there is a pressing need to develop a comprehensive public health approach for SLD. To that end, we propose a public health framework for preventing and controlling SLD. The framework is anchored on evidence linking physical inactivity, unhealthy dietary patterns, alcohol use, and obesity with both incidence and progression of SLD. Guided by the framework, we review examples of federal/state, community, and individual-level interventions with the potential to address these determinants of SLD. Ultimately, mitigating SLD’s burden requires primary risk factor reduction at multiple socioecological levels, by scaling up the World Health Organization’s “best buys”, in addition to developing and implementing SLD specific control interventions.

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A landscape of liver cirrhosis and transplantation in Mexico: Changing leading causes and transplant as response

Palma-Lara,

Ortiz-López,

Bonilla-Delgado

et al. 2025

Annals of Hepatology

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Alcohol-associated liver disease: Epidemiology and management

Cited by 13 publications

References 117 publications

Delineating the heterogeneity of senescence-induced-functional alterations in hepatocytes

Delineating the heterogeneity of senescence-induced-functional alterations in hepatocytes

A public health perspective on mitigating the global burden of chronic liver disease

A landscape of liver cirrhosis and transplantation in Mexico: Changing leading causes and transplant as response

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