Cholestatic liver diseases, marked by harmful bile acid accumulation, pose serious health challenges, significantly affecting liver function and overall health. A recent study sheds light on how chenodeoxycholic acid (CDCA) interacts with liver endothelial cells (ECs) to exacerbate liver injury through the farnesoid X receptor (FXR) and Myc signaling pathways.
Researchers conducted this investigation by analyzing single-cell RNA sequencing data from various murine models, identifying distinct activation of the Myc signaling pathway within ECs during obstructive cholestasis induced by bile duct ligation (BDL). This activation of Myc contributes to the upregulation of P-selectin, leading to increased neutrophil infiltration and worsening liver injury.
Typically, bile acids play dual roles; they are not only involved in digestion but also act as signaling molecules affecting both immune and cellular pathways. Traditionally perceived primarily as detergents damaging cellular membranes, they are now recognized for their more nuanced roles within the liver's complex environment. Yet, the precise interactions influencing liver damage due to bile acid accumulation remain unclear.
The research identified key roles of liver ECs, the most abundant non-parenchymal cells accounting for 15-20% of liver cells, acting as gatekeepers of liver immunity. Physiologically, these cells facilitate blood flow regulation and selectively transport molecules and immune cells to hepatic tissue, offering insights on how they might modulate immune responses amid cholestatic liver diseases.
Leveraging single-cell transcriptomic profiling from healthy and various cholestatic murine liver injury models, the research revealed significant Myc expression elevation particularly prominent during BDL-induced cholestasis. Myc, being implicated as a driver of cellular growth and metabolism, was found to be upregulated, prompting explorations around its downstream effects.
To investigate the biological consequences of Myc overexpression within the liver’s endothelium, transgenic mice with endothelial-specific Myc overexpression were engineered. Results highlighted notable neutrophil recruitment associated with elevated Myc activity. Quantifying inflamed areas, significant increases of neutrophils were observed, denoting the inflammatory response linked to Myc and P-selectin activation.
An intriguing aspect of the findings is the clinical relevance observed through patient liver samples, showcasing similar elevations of Myc and P-selectin correlated with heightened neutrophil presence. "Cholestatic patient liver samples also show elevated Myc and P-selectin in ECs, along with increased neutrophils," wrote the authors of the article, underscoring the translational potential of this study.
The research also explored therapeutic avenues, evidencing the potential for P-selectin inhibition as a strategy to mitigate liver damage. Employing PSI-697, a P-selectin inhibitor, the study demonstrated alleviated liver injury and inflammation, reinforcing the premise of targeting the CDCA/FXR/Myc/P-selectin axis as valuable intervention points for cholestatic liver injuries.
Further investigation revealed CDCA as a potent trigger of the MYC/P-selectin axis through FXR. Specific responses of ECs to CDCA emphasized its role as not only a bile acid but also as a significant regulatory molecule during cholestatic events. Exposing human umbilical vein endothelial cells (HUVECs) to various bile acid components solidified the necessity of FXR activation for upregulating MYC and P-selectin expressions.
Given the backdrop of enhanced immune interventions observed, the findings contribute to the broader narrative surrounding liver diseases, highlighting how dysregulation of EC functions during cholestasis could diminish liver protective mechanisms. The research aligns with the calls for innovative immuno-therapeutic strategies targeting pathways like MYC/P-selectin to ameliorate cholestatic liver disease outcomes.
Future investigations may refine these findings, focusing on patient-derived insights to elucidate pathogenic mechanisms underlying cholestasis. The collective findings pinpoint the endothelial CDCA/FXR/Myc/P-selectin regulatory pathways, offering potential therapeutic promises aimed at enhancing patient outcomes and preventing severe liver injuries associated with cholestatic conditions.