image: In response to alcohol, various cellular and molecular changes occur in the liver, contributing to hepatic steatosis, inflammation and fibrosis. Hepatocytes exhibit increased production of reactive oxygen species (ROS) and release damage-associated molecular patterns (DAMPs) along with extracellular vesicles (EVs) containing mitochondrial DNA (mtDNA), microRNA (miRNA) and CD40 ligand (CD40L). This, combined with a reduced NAD+/NADH ratio, promotes the development of hepatic steatosis, inflammation and fibrosis. Macrophages work alongside neutrophils to clear cellular debris; however, continuous alcohol consumption activates macrophages, leading to hepatic inflammation through cytokine secretion and phagocytosis. Kupffer cells (KCs) also contribute to this inflammation by activating hepatic stellate cells (HSCs). A reduced expression of complement receptor of the immunoglobulin superfamily (CRIg) on macrophages has been linked to the progression of ALD. Moreover, interleukin (IL)-1β-containing EVs derived from hepatic macrophages have been implicated in alcohol-induced liver injury and steatosis. Neutrophils contribute to inflammation in ALD through mechanisms such as ROS production, phagocytosis, cytokine release, degranulation and the formation of neutrophil extracellular traps (NETs). Various T cells in the liver, including T helper (Th) 17 cells, regulatory T cells (Tregs), natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells, also play important roles in liver injury in response to alcohol exposure. HSCs respond to alcohol by producing increased amounts of extracellular matrix (ECM) and transforming growth factor-beta (TGF-β), leading to liver fibrosis. Alcohol stimulates HSCs to produce 2-arachidonoylglycerol (2-AG), which binds to cannabinoid receptor 1 (CB1R) on hepatocytes, promoting steatosis. Interestingly, HSCs deficient in neuropilin-1 (NRP-1) have been shown to reduce hepatic steatosis, inflammation and fibrosis in murine models of ALD. Additionally, TGF-β produced by activated HSCs can polarise macrophages towards an M2 phenotype, which exhibits anti-inflammatory functions.
Credit: By Hui Gao, Yanchao Jiang, Ge Zeng, Nazmul Huda, Themis Thoudam, Zhihong Yang, Suthat Liangpunsakul, Jing Ma
A newly published review in eGastroenterology compiles recent research on alcohol-associated liver disease (ALD), offering an overview of its pathogenesis and efforts to better understand this condition. ALD, caused by excessive alcohol consumption, remains a significant contributor to liver-related mortality worldwide. Effective treatments are still limited, underscoring the need for a deeper understanding of its mechanisms. This review summarizes findings on the cellular, molecular, and systemic processes involved in ALD progression, with a focus on liver cell interactions, immune responses, and inter-organ communication.
The review examines how alcohol metabolism affects liver function, focusing on the roles of oxidative stress and inflammation in driving liver injury. Alcohol metabolism in hepatocytes generates reactive oxygen species (ROS) and toxic byproducts such as acetaldehyde, which can damage liver cells and trigger immune responses. Activation of Kupffer cells (liver-resident macrophages) and hepatic stellate cells (HSCs) contributes to inflammation and fibrosis, which are key features of ALD progression. The review highlights these pathways as areas of interest for future research.
A notable focus of the review is the role of extracellular vesicles (EVs) in intercellular communication. These nanoscale particles, released by damaged liver cells, carry molecular signals that can influence both neighboring and distant cells. EVs are implicated in modulating immune responses, activating HSCs, and promoting fibrosis, suggesting their involvement in ALD progression. The review also discusses recent studies identifying EVs as potential biomarkers for early diagnosis and as possible targets for therapeutic intervention.
The review discusses the gut-liver axis as an important pathway in the development of ALD. Alcohol-induced changes in gut microbiota, known as dysbiosis, can increase intestinal permeability, allowing bacterial products like lipopolysaccharides (LPS) to reach the liver. These microbial products may activate inflammatory pathways, contributing to liver injury. This interaction between the gut and liver underscores the systemic nature of ALD and suggests potential avenues for therapies that address both gut and liver health.
The review discusses the role of cytokines, signaling molecules involved in regulating inflammation and immune responses, in ALD. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-17, contribute to liver injury by promoting inflammation and recruiting immune cells. Anti-inflammatory cytokines, like IL-10, work to counteract this response but may be insufficient during chronic alcohol exposure. Exploring the interplay between these opposing forces could provide insights into potential strategies for modulating the immune response to reduce liver damage.
The review also considers the broader impact of ALD, highlighting its effects on other organs and systems beyond the liver. It discusses the interactions between the liver, gut, adipose tissue, and the immune system. For instance, free fatty acids and adipokines released from adipose tissue may contribute to hepatic steatosis and inflammation. These connections suggest the importance of a comprehensive approach to understanding and addressing ALD.
This review provides a comprehensive synthesis of current knowledge, summarizing data from various studies to offer an overview of the pathogenesis of ALD and identify areas where further research is needed. The perspective presented aims to inform future studies and contribute to the development of diagnostic and therapeutic approaches.
“This review is a testament to the progress made in understanding ALD,” said Dr. Hui Gao, the first author of the review. “It highlights not only the complexity of the disease but also the opportunities for intervention through targeted therapies.”
See the article:
Gao H, Jiang Y, Zeng G, et al. Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease. eGastroenterology 2024;2:e100104. doi:10.1136/egastro-2024-100104
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Journal
eGastroenterology
Article Title
Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease