Liver Stiffness Directs Intrahepatic Cholesterol Accumulation Through YAP/TAZ in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Summary

Liver stiffness mechanotransduces cholesterol accumulation by activating YAP/TAZ, which repress LXRα and disrupt LXRα–RXRα heterodimerization, driving hepatocyte cholesterol loading. Human and mouse data converge, and hepatocyte-specific Yap/Taz ablation enhances cholesterol efflux and attenuates fibrosis progression.

Key Findings

• In human MASLD and mouse models, intrahepatic cholesterol strongly correlates with liver stiffness.
• Stiff matrices drive spontaneous cholesterol accumulation in isolated hepatocytes.
• YAP/TAZ activation mechanosensitively represses LXRα and disrupts LXRα–RXRα heterodimerization.
• Hepatocyte-specific Yap/Taz ablation enhances cholesterol efflux and delays cholesterol-induced fibrosis.
• Patient liver transcriptomics show inverse correlation between LXRα target genes and stiffness/YAP-TAZ activity.

Clinical Implications

Noninvasive stiffness metrics may predict cholesterol-driven hepatocyte dysfunction; targeting mechanotransduction (e.g., YAP/TAZ modulators) or restoring LXRα activity could mitigate cholesterol accumulation and fibrosis in MASLD.

Limitations

• Human data are correlative; interventional proof in patients is pending
• Translatability of stiffness-modulating or YAP/TAZ-targeting therapies requires safety and efficacy studies

Future Directions

Evaluate pharmacologic YAP/TAZ or LXRα modulators in MASLD; integrate elastography with lipidomic biomarkers to stratify risk and monitor response.