AhR activation leading to liver fibrosis

Xavier Coumoul^*, Min Ji Kim^$, Karine Audouze*, Etienne Blanc^*, Jean-Pascal de Bandt^*

Institutions : Université Paris Cité^*, Université Sorbonne Nord^$ / Inserm T3S Umr-S 1124

Liver fibrosis, characterized by excessive accumulation of extracellular matrix proteins, represents a significant health burden worldwide. The Ah receptor (AhR), a ligand-activated transcription factor primarily known for its involvement in xenobiotic metabolism, has emerged as a key player in various physiological processes, including liver homeostasis and inflammation. Recent studies have implicated the AhR signaling pathway in the development and progression of liver fibrosis. This AOP provides a comprehensive overview of the molecular mechanisms underlying the association between AhR activation and liver fibrogenesis. AhR activation by endogenous ligands, such as tryptophan metabolites and environmental toxins, triggers a cascade of events leading to hepatic stellate cell activation, inflammation, and fibrogenesis. Understanding the intricate interplay between AhR and liver fibrosis offers novel insights into the pathogenesis of chronic liver diseases and highlights AhR as a potential therapeutic target for the management of liver fibrosis.

Understanding the biological link between Ah receptor (AhR) activation and liver fibrosis holds significant relevance due to its implications in the pathogenesis of various liver diseases. Liver fibrosis represents a common pathological process underlying the progression of chronic liver disorders, including hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD). Notably, NAFLD, characterized by hepatic steatosis, inflammation, and fibrosis, has become a global health concern, closely associated with obesity, metabolic syndrome, and insulin resistance. Given that AhR activation has been implicated in the regulation of lipid metabolism and inflammation, elucidating its role in liver fibrosis provides valuable insights into the molecular mechanisms driving NAFLD progression. Moreover, the interconnected nature of liver diseases underscores the importance of investigating AhR-mediated pathways as potential therapeutic targets for the management of liver fibrosis and its comorbidities, including hepatic steatosis. Therefore, establishing a biological link between AhR activation and liver fibrosis not only enhances our understanding of disease pathogenesis but also offers promising avenues for the development of targeted therapies for liver-related disorders.

We have been working for many years on chronic liver diseases and AhR. We had written a review on the subject and, following on from experimental work showing the links between AhR and fibrosis (two publications), we decided as part of the PARC project to take advantage of this expertise to publish this AOP. 

The biological plausibility of KERs is defined by the OECD as the « understanding of the fundamental biological processes involved and whether they are consistent with the causal relationship being proposed in the AOP ». The biological plausibility is strong due to the presence of overwhelming evidence present in different studies. A minor setback would be the difficulty to dismiss alternative mechanisms caused by the ligands used for AhR activation. 

The essentiality of KEs refers to « experimental data for whether or not downstream KEs or the AO are prevented or modified if an upstream event is blocked ». The essentiality of KEs is strong: most works converge to imply the AhR in fibrotic processes. One setback would be that AhR knockout mice also develop a specific liver fibrosis. We propose that exogenous ligands alter the activity of endogenous ligands and therefore contribute just like the knockout to the occurence of liver fibrosis. The AhR activation needs to be considered then as the binding of exogenous ligands (xenobiotics) counteracting on the physiological processes which regulate the physiological functions.

Finally, the empirical support of KERs, is often « based on toxicological data derived by one or more reference chemicals where dose–response and temporal concordance for the KE pair can be assessed ». The overall assessment of the empirical support of our KERs is also strong. There is evidence in human cell lines and mice showing a dose–response and temporal concordance for severity of our KEs and the adverse outcomes (for example, a dose-dependant effect of TCDD on the development of liver fibrosis in mice).