Roles of the complement system in alcohol-induced liver disease

Zhou, Yi; Yuan, Guandou; Zhong, Fan; He, Songqing

doi:10.3350/cmh.2020.0094

Cited by 17 publications

(7 citation statements)

References 58 publications

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“…Neuroimmune pathways were commonly enriched for multiple SE events, including TNF, NF- κB, IL6-JAK-STAT3, IL2-STAT5, NOD-like receptor (NLR) signaling pathways, as well as T cell activation and differentiation (Supplementary Table S6 ). Noteworthy, the complement cascade, which is part of the innate immune system involved in alcoholic liver disease [ 62 ], was enriched for the SE events in ELOVL7, LINC00665 , NSUN4 , and SRRM2 . We also found that epithelial-mesenchymal transition (EMT) was enriched for the SE events in ELOVL7 , SRRM2 and TBC1D5 and was depleted for DRC1 and LINC00665 in GSEA.…”

Section: Resultsmentioning

confidence: 99%

RNA alternative splicing impacts the risk for alcohol use disorder

Reiter

Chen

et al. 2023

Mol Psychiatry

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Alcohol use disorder (AUD) is a complex genetic disorder characterized by problems arising from excessive alcohol consumption. Identifying functional genetic variations that contribute to risk for AUD is a major goal. Alternative splicing of RNA mediates the flow of genetic information from DNA to gene expression and expands proteome diversity. We asked whether alternative splicing could be a risk factor for AUD. Herein, we used a Mendelian randomization (MR)-based approach to identify skipped exons (the predominant splicing event in brain) that contribute to AUD risk. Genotypes and RNA-seq data from the CommonMind Consortium were used as the training dataset to develop predictive models linking individual genotypes to exon skipping in the prefrontal cortex. We applied these models to data from the Collaborative Studies on Genetics of Alcoholism to examine the association between the imputed cis-regulated splicing outcome and the AUD-related traits. We identified 27 exon skipping events that were predicted to affect AUD risk; six of these were replicated in the Australian Twin-family Study of Alcohol Use Disorder. Their host genes are DRC1, ELOVL7, LINC00665, NSUN4, SRRM2 and TBC1D5. The genes downstream of these splicing events are enriched in neuroimmune pathways. The MR-inferred impacts of the ELOVL7 skipped exon on AUD risk was further supported in four additional large-scale genome-wide association studies. Additionally, this exon contributed to changes of gray matter volumes in multiple brain regions, including the visual cortex known to be involved in AUD. In conclusion, this study provides strong evidence that RNA alternative splicing impacts the susceptibility to AUD and adds new information on AUD-relevant genes and pathways. Our framework is also applicable to other types of splicing events and to other complex genetic disorders.

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Section: Resultsmentioning

confidence: 99%

RNA alternative splicing impacts the risk for alcohol use disorder

Reiter

Chen

et al. 2023

Mol Psychiatry

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“…Ethanol can be metabolized to ROS by alcohol dehydrogenase (ADH) and Advances in Pharmacological and Pharmaceutical Sciences CYP2E1 [68]. ROS are released extensively, triggering toxic efects directly or indirectly through lipid peroxides [69]. A recent study reported that ethanol-induced liver injury and lipid peroxidation correlate with the CYP2E1 activity [70].…”

Section: Kaempferol Suppresses the Hepatic Activity Of Cyp2e1mentioning

confidence: 99%

Hepatoprotective Effect of Kaempferol: A Review of the Dietary Sources, Bioavailability, Mechanisms of Action, and Safety

Alkandahri

Pamungkas

Oktoba

et al. 2023

Advances in Pharmacological and Pharmaceutical Sciences

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The liver is the body’s most critical organ that performs vital functions. Hepatic disorders can affect the physiological and biochemical functions of the body. Hepatic disorder is a condition that describes the damage to cells, tissues, structures, and functions of the liver, which can cause fibrosis and ultimately result in cirrhosis. These diseases include hepatitis, ALD, NAFLD, liver fibrosis, liver cirrhosis, hepatic failure, and HCC. Hepatic diseases are caused by cell membrane rupture, immune response, altered drug metabolism, accumulation of reactive oxygen species, lipid peroxidation, and cell death. Despite the breakthrough in modern medicine, there is no drug that is effective in stimulating the liver function, offering complete protection, and aiding liver cell regeneration. Furthermore, some drugs can create adverse side effects, and natural medicines are carefully selected as new therapeutic strategies for managing liver disease. Kaempferol is a polyphenol contained in many vegetables, fruits, and herbal remedies. We use it to manage various diseases such as diabetes, cardiovascular disorders, and cancers. Kaempferol is a potent antioxidant and has anti-inflammatory effects, which therefore possesses hepatoprotective properties. The previous research has studied the hepatoprotective effect of kaempferol in various hepatotoxicity protocols, including acetaminophen (APAP)-induced hepatotoxicity, ALD, NAFLD, CCl4, HCC, and lipopolysaccharide (LPS)-induced acute liver injury. Therefore, this report aims to provide a recent brief overview of the literature concerning the hepatoprotective effect of kaempferol and its possible molecular mechanism of action. It also provides the most recent literature on kaempferol’s chemical structure, natural source, bioavailability, and safety.

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“…For instance, C3, factor B, and factor D activate the alternative pathway, leading to the generation of anaphylatoxins C3a and C5a, which induce insulin resistance and disrupt lipid metabolism in the liver ( 352 ). C1q contributes to liver injury by activating the classical complement, whereas factor D protects against ethanol-induced inflammation and promotes hepatic healing and recovery ( 353 , 354 ). Several experimental models have demonstrated that complement inhibition is beneficial for liver injury (including IRI), liver transplantation, and acute liver failure.…”

Section: Liver and Diseasesmentioning

confidence: 99%

Interorgan communication with the liver: novel mechanisms and therapeutic targets

Zhao,

Zhang,

et al. 2023

Front. Immunol.

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The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as “hepatokines”). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body’s innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.

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Roles of the complement system in alcohol-induced liver disease

Cited by 17 publications

References 58 publications

RNA alternative splicing impacts the risk for alcohol use disorder

RNA alternative splicing impacts the risk for alcohol use disorder

Hepatoprotective Effect of Kaempferol: A Review of the Dietary Sources, Bioavailability, Mechanisms of Action, and Safety

Interorgan communication with the liver: novel mechanisms and therapeutic targets

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