Roles of the complement system in alcohol-induced liver disease.
- Authors
- Zhou, Yi; Yuan, Guandou; Zhong, Fudi; He, Songqing
- Year
- 2020
- Journal
- Clinical and molecular hepatology
- PMID
- 33053939
- DOI
- 10.3350/cmh.2020.0094
- PMCID
- PMC7641541
Alcohol-induced liver disease (ALD) is a complex disorder, with a disease spectrum ranging from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Although the pathogenesis of ALD is incompletely understood and currently no effective drugs are available for ALD, several lines of evidence suggest that complement activation and oxidative stress play crucial roles in the pathogenesis of ALD. Complement activation can regulate the production of ROS and influence oxidative stress in ALD. Precise regulation of the complement system in ALD may be a rational and novel avenue to postpone and even reverse the progression of disease and simultaneously promote the repair of liver injury. In this mini-review, we briefly summarize the recent research progress, especially focusing on the role of complement and oxidative stress-induced transfer RNA-derived fragments, which might help us to better understand the pathogenesis of ALD and provide aid in the development of novel therapeutic strategies for ALD.
Schematic overview of the complement cascade illustrating three activation pathways (classical, lectin, and alternative) and summarizing the biological effects of complement activation products. MAC, membrane attack complex.
Schematic of CR2 site-targeted complement inhibitors. The CR2 moiety of the fusion protein binds the C3 degradation products iC3b, C3dg, and C3d that are covalently attached at sites of complement activation. Complement inhibitory constructs that have previously been prepared and characterized are CR2-Crry (murine inhibitor of C3 activation), CR2-CR1 (human inhibitor of C3 activation), CR2-fH (murine and human inhibitor of the alternative complement pathway), and CR2-CD59 (murine and human inhibitor of MAC formation). F1, factor 1; SP, serum protease; CR1/2, complement receptor 1/2; Crry, complement receptor-1 related protein y.
Schematic graph showing that the complement system participates in the development of alcohol-induced liver disease. C3 convertase cleaves C3 to form C3a and C3b. ASP is the degraded product of C3a. C3b is an important component of C5 convertase. CR2-Crry is a site-targeted complement inhibitor that blocks all complement pathways at the C3 activation step. When anaphylatoxins C3a and C5a bind with their respective receptors, the TLR4/NF-κB pathway can be activated, resulting in the release of the inflammatory cytokine TNF-α, which participates in AFLD, either directly or indirectly, through the induction of insulin resistance. C3a and ASP bind to their receptor C5aR2 to promote the expression of Cyp2E1, which induces the production of ROS. The induced oxidative stress subsequently leads to the increased expression of Gly-tRF, which leads to AFLD via regulating the SIRT1 signaling pathway. The inflammatory response contributes to the development and progression of ALD. CR2, complement receptor 2; Crry, complement receptor 1-related protein y; ASP, acylation stimulating protein; Cyp2E1, cytochrome P450 family 2, subfamily E, polypeptide 1; GlytRFs, glycine tRNA-derived fragments; ROS, reactive oxygen species; TLR, toll-like receptor; TNF-α, tumor necrosis factor-alpha; AFLD, alcoholic fatty liver disease; ALD, alcohol-induced liver disease.
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| Discovering Heterogeneous Leukocytes Subsets Associated With Alcoholic Steatohepatitis by scRNAseq Analysis. | Perumalsamy H et al. | — | 2025 | → |
| Flavonoid Polyphenols as Therapeutic Agents for Fatty Liver Disease: Mechanisms, Microbiome Interactions, and Metabolic Insights. | Li L et al. | — | 2025 | → |
| Gardenin A alleviates alcohol-induced oxidative stress and inflammation in HepG2 and Caco2 cells via AMPK/Nrf2 pathway. | Chadha P et al. | — | 2025 | → |
| Novel insights into cuproptosis in alcoholic liver disease using bioinformatics analysis and experimental validation. | Pan T et al. | — | 2025 | → |
| Reactive Oxygen Species as Key Molecules in the Pathogenesis of Alcoholic Fatty Liver Disease and Nonalcoholic Fatty Liver Disease: Future Perspectives. | Zhang Z et al. | — | 2025 | → |
| Research progress on the roles of complement in liver injury. | Ou LL et al. | — | 2025 | → |
| The activation of microglia by the complement system in neurodegenerative diseases. | Zhao H et al. | — | 2025 | → |
| Alcohol and Periodontal Disease: A Narrative Review. | Gandhi UH et al. | — | 2024 | → |
| DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease. | Magdy A et al. | — | 2024 | → |
| Hepatocyte-derived Fetuin-A promotes alcohol-associated liver disease in mice by inhibiting autophagy-lysosome degradation of TLR and M2 macrophage polarization. | Lu S et al. | — | 2024 | → |
| Inflammatory liver diseases and susceptibility to sepsis. | Lu H | — | 2024 | → |
| Shear Wave Dispersion Elastography in ALD and MASLD: Comparative Pathophysiology and Clinical Potential-A Narrative Review. | Dionisi T et al. | — | 2024 | → |
| Water decoction of <i>Pericarpium citri reticulatae</i> and <i>Amomi fructus</i> ameliorates alcohol-induced liver disease involved in the modulation of gut microbiota and TLR4/NF-κB pathway. | Zhang XM et al. | — | 2024 | → |
| Hepatoprotective Effect of Kaempferol: A Review of the Dietary Sources, Bioavailability, Mechanisms of Action, and Safety. | Alkandahri MY et al. | — | 2023 | → |
| Hydrogen gas ameliorates acute alcoholic liver injury via anti-inflammatory and antioxidant effects and regulation of intestinal microbiota. | Liu H et al. | — | 2023 | → |
| Interorgan communication with the liver: novel mechanisms and therapeutic targets. | Zhao J et al. | — | 2023 | → |
| RNA alternative splicing impacts the risk for alcohol use disorder | Liu Y et al. | — | 2023 | — |
| RNA alternative splicing impacts the risk for alcohol use disorder. | Li R et al. | — | 2023 | → |
| Immune cells in alcohol-related liver disease. | Xu H et al. | — | 2022 | → |
| Complement in Acute Liver Failure: The Right Timing to Give a Sincere Compliment. | Weber SN et al. | — | 2021 | → |
| Complement System in Alcohol-Associated Liver Disease. | Santiesteban-Lores LE et al. | — | 2021 | → |
| Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression. | Chang ML et al. | — | 2020 | → |