Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia

Area of Science:

• Toxicology and Pharmacology
• Molecular Biology
• Environmental Health

Background:

• Hypercholesterolemia, a significant risk factor for atherosclerosis and global health burden, can be induced by pharmaceuticals and environmental contaminants.
• The pregnane X receptor (PXR) is a nuclear receptor involved in detoxification, but its activation is increasingly linked to metabolic disruptions, including hypercholesterolemia.

Purpose of the Study:

• To construct an Adverse Outcome Pathway (AOP) detailing the molecular mechanisms by which PXR activation leads to hypercholesterolemia.
• To systematize knowledge on PXR-mediated hypercholesterolemia for improved chemical risk assessment.

Main Methods:

• Literature review and knowledge synthesis to establish key events and relationships.
• Construction of a linear AOP framework linking a molecular initiating event (MIE) to an adverse outcome (AO).

Main Results:

• PXR activation serves as the molecular initiating event (MIE) for the described adverse outcome pathway.
• Hypercholesterolemia is identified as the adverse outcome (AO), mediated through PXR's regulation of cholesterol synthesis and the sterol regulatory element binding protein 2 (SREBP-2) pathway.

Conclusions:

• PXR activation represents a novel toxicity pathway contributing to hypercholesterolemia.
• The developed AOP provides a mechanistic framework for understanding and assessing the risks associated with PXR-activating chemicals.