Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression

Osna, Natalia A.; Tikhanovich, Irina; Ortega-Ribera, Martí; Mueller, Sebastian; Zheng, Chaowen; Mueller, Johannes; Li, Siyuan; Sakane, Sadatsugu; Weber, Raquel Carvalho Gontijo; Kim, Hyun Young; Lee, Wonseok; Ganguly, Souradipta; Kimura, Yusuke; Liu, Xiao; Dhar, Debanjan; Diggle, Karin; Brenner, David A.; Kisseleva, Tatiana; Attal, Neha; McKillop, Iain H.; Chokshi, Shilpa; Mahato, Ram; Rasineni, Karuna; Szabo, Gyongyi; Kharbanda, Kusum K.

doi:10.3390/biom14040404

Biomolecules

2024

DOI: 10.3390/biom14040404

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Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression

Natalia A. Osna,

Irina Tikhanovich,

Martí Ortega-Ribera

et al.

Abstract: Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid … Show more

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2024

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Cited by 3 publications

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Gegen-Sangshen oral liquid and its active fractions mitigate alcoholic liver disease in mice through repairing intestinal epithelial injury and regulating gut microbiota

Wei,

Li,

Zhao

et al. 2024

Chin Med

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Background Liuweizhiji Gegen-Sangshen oral liquid (LGS), as a Chinese medicinal preparation, is developed from a Traditional Chinese medicinal formula consisting of six Chinese medicinal herbs, including Puerariae lobatae radix, Hoveniae semen, Imperatae rhizoma, Crataegi fructus, Mori fructus and Canarli fructus, and has been extensively utilized in the prevention and treatment of alcoholic liver disease (ALD) clinically. Previous study has demonstrated that LGS dose-dependently mitigated ALD in rat models. However, whether and how the main characteristic constituents of LGS (the flavonoid and polysaccharide fractions, LGSF and LGSP) contribute to the anti-ALD effect remains unclear. This study aimed to assess the anti-ALD effect of LGS and its main fractions (LGSF and LGSP) in a murine model of ALD and to explore the underlying mechanisms. Methods ALD mouse model was constructed using the chronic and binge ethanol feeding method. Biochemical determinations of AST, ALT, TC, TG, ADH, ALDH, HDL, LDL, IL-1β, IL-6, and TNF-α were performed using corresponding kits. Histopathological examination of liver and intestinal sections was conducted based on the H&E staining. Lipid accumulation in hepatocytes was evaluated by oil red O staining. Ethanol metabolism was assessed by determining the activity of ADH and ALDH enzymes. Intestinal barrier function was analyzed based on immunohistochemistry analysis of ZO-1 and occludin and immunofluorescence analysis of epithelial markers, Lgr5, Muc2, and Lyz1. Intestinal epithelial apoptosis was detected by TUNEL staining. Mouse fecal microbiota alterations were analyzed by 16S rRNA sequencing. An in vitro epithelial injury model was established by developing TNF-α-induced 3D-cultured intestinal organoids. In vitro culture of specific bacterial strains was performed. Results The results showed that LGS and its flavonoid and polysaccharide fractions (LGSF and LGSP) significantly alleviated ALD in mice through attenuating hepatic injury and inflammation, improving liver steatosis and promoting ethanol metabolism. Notably, LGS, LGSP, and LGSF mitigated intestinal damage and maintained barrier function in ALD mice. The intestinal barrier protection function of LGS, LGSP, and LGSF was generally more obvious than that of the positive drug meltadosine. Further study demonstrated that LGS, LGSP, and LGSF promoted intestinal epithelial repair via promoting Lgr5+ stem cell mediated regeneration in TNF-α-induced intestinal organoids. LGS and LGSF, other than LGSP, had a better effect on repair of epithelial injury in vitro. Moreover, LGS, LGSP, and LGSF remarkably alleviated gut dysbiosis in ALD mice via at least partially recovery of alcohol-induced microbial changes and induction of specific bacterial groups. In vitro culture of bacterial strains indicated that LGS, LGSP, and LGSF had a specific impact on bacterial growth. LGS and LGSP, but not the LGSF, significantly promoted the growth of Lactobacillus. Similarly, LGS and LGSP significantly increased the proliferation of Bacteroides sartorii, and LGSF had a minimal effect. LGS, LGSP and LGSF all promoted the growth of Bacillus coagulans, Bifidobacterium adolescentis, and Bifidobacterium bifidum. LGS and LGSP promoted the growth of Dubosiella newyorkensis, but the LGSF had no effect. Conclusions LGS exerts its anti-ALD effect in mice through regulating gut-liver axis, and its flavonoid and polysaccharide fractions, LGSF and LGSP, are responsible for its protective effect.

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Gegen-Sangshen oral liquid and its active fractions mitigate alcoholic liver disease in mice through repairing intestinal epithelial injury and regulating gut microbiota

Wei,

Li,

Zhao

et al. 2024

Chin Med

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Electrical and Viscoelastic Parameters of Erythrocytes as a Part of Diagnostic Models for Differentiating Fatty Liver Disease of Mixed Genesis from Non-Alcoholic and Alcohol-Related Fatty Liver Disease

Kruchinina,

Osipenko,

Parulikova

et al. 2024

Rossijskij žurnal gastroènterologii, gepatologii, koloproktolog

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Aim: creation of diagnostic models including electrical, viscoelastic parameters of erythrocytes to distinguish fatty liver disease of mixed etiology (metabolic + alcoholic) from non-alcoholic and alcoholic fatty liver disease.Materials and methods. We examined 46 men with non-alcoholic fatty liver disease (NAFLD), 43 men with alcoholic fatty liver disease (AFLD), as well as 54 men with fatty liver disease (FLD) of mixed genesis (metabolic + alcohol-related); average age of the patients included in the study made 48.4 ± 9.6 years. The diagnosis was established on the basis of liver ultrasound findings and FLI liver steatosis index with a fibrosis grade of F1 or less (FibroScan® 502, Echosens, France). The electrical and viscoelastic parameters of erythrocytes were investigated by the diagnostic technique of dielectrophoresis using an electrooptical cell detection system.Results. The most significant parameters for differentiating fatty liver disease of mixed genesis (metabolic + alcoholic) from NAFLD using the Volcano plot have turned out to be cell polarizability at a frequency of 106 Hz (p = 6.49 ×10-5), erythrocyte cell membrane capacity (p = 0.00077), relative polarizability (p = 0.001), the levels of which were higher in patients with NAFLD. On the contrary, the index of red blood cells destruction at 105 Hz was higher in FLD of the mixed genesis (p = 0.047) and the crossover frequency was shifted to the high frequency range more than in NAFLD (p = 0.0005). The discriminant analysis has additionally revealed the significance of the degree of erythrocyte deformation at 5 ×105 Hz in distinguishing between mixed-genesis FLD and NAFLD. In differentiating FLD of mixed genesis from NAFLD, a diagnostic model incorporating the above red blood cells parameters has provided an AUC of 0.829 (confidential interval: 0.742–0.916), sensitivity of 80.9 %, and specificity of 83.3 %. Two indicators of red blood cells have been established that statistically significantly distinguish the mixed-genesis FLD from the AFLD (Volcano plot); these are the index of red blood cells destruction at a frequency of 5 ×105 Hz, which was higher with AFLD (p = 0.0007), and the capacity of cell membranes, the value of which prevailed in mixed-genesis FLD (p = 0.011). When distinguishing the mixed-genesis FLD from the AFLD, the combined model with the inclusion of three parameters of red blood cells, namely the index of red blood cells destruction at a frequency of 5 ×105 Hz, the capacity of erythrocyte membranes, and polarizability at a frequency of 106 Hz, has shown the highest levels of diagnostic accuracy, namely AUC = 0.751 (confidential interval: 0.611–0.908) with a sensitivity of 79.5 %, specificity of 74.7 %.Conclusion. The electrical and viscoelastic parameters of erythrocytes studied using the diagnostic technique of dielectrophoresis should be considered as promising biomarkers for the diagnosis of diffuse liver disease.

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Understanding the Role of Alcohol in Metabolic Dysfunction and Male Infertility

Genchi,

Cignarelli,

Sansone

et al. 2024

Metabolites

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Purpose: Over the past 40–50 years, demographic shifts and the obesity epidemic have coincided with significant changes in lifestyle habits, including a rise in excessive alcohol consumption. This increase in alcohol intake is a major public health concern due to its far-reaching effects on human health, particularly on metabolic processes and male reproductive function. This narrative review focuses on the role of alcohol consumption in altering metabolism and impairing testicular function, emphasizing the potential damage associated with both acute and chronic alcohol intake. Conclusion: Chronic alcohol consumption has been shown to disrupt liver function, impair lipid metabolism, and dysregulate blood glucose levels, contributing to the development of obesity, metabolic syndrome, and related systemic diseases. In terms of male reproductive health, alcohol can significantly affect testicular function by lowering testosterone levels, reducing sperm quality, and impairing overall fertility. The extent of these effects varies, depending on the frequency, duration, and intensity of alcohol use, with chronic and abusive consumption posing greater risks. The complexity of alcohol’s impact is further compounded by individual variability and the interaction with other lifestyle factors such as diet, stress, and physical activity. Despite growing concern, research on alcohol’s effects remains inconclusive, with significant discrepancies across studies regarding the definition and reporting of alcohol consumption. These inconsistencies highlight the need for more rigorous, methodologically sound research to better understand how alcohol consumption influences metabolic and reproductive health. Ultimately, a clearer understanding is essential for developing targeted public health interventions, particularly in light of rising alcohol use, demographic changes, and the ongoing obesity crisis.

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Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression

Cited by 3 publications

References 207 publications

Gegen-Sangshen oral liquid and its active fractions mitigate alcoholic liver disease in mice through repairing intestinal epithelial injury and regulating gut microbiota

Gegen-Sangshen oral liquid and its active fractions mitigate alcoholic liver disease in mice through repairing intestinal epithelial injury and regulating gut microbiota

Electrical and Viscoelastic Parameters of Erythrocytes as a Part of Diagnostic Models for Differentiating Fatty Liver Disease of Mixed Genesis from Non-Alcoholic and Alcohol-Related Fatty Liver Disease

Understanding the Role of Alcohol in Metabolic Dysfunction and Male Infertility

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