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

ABSTRACT Elevated liver stiffness is closely associated with morbidity and mortality in metabolic dysfunction‐associated steatotic liver disease (MASLD). However, the contribution of increased stiffness to impaired liver function is poorly understood. Here, we demonstrate that hepatic cholesterol levels are determined by the stiffness of the liver. In the human MASLD cohort and a mouse model, intrahepatic cholesterol levels strongly correlated with liver stiffness. We show that a stiff matrix promotes spontaneous accumulation of cholesterol in isolated hepatocytes. As the underlying mechanism, we found that Liver X receptor alpha (LXRα) is mechanosensitively repressed. Activation of Yes‐associated protein (YAP) and Transcriptional coactivator with PDZ‐binding motif (TAZ) by exposure to stiff substrate, serum stimulation, low‐density culture, or deletion of Large tumor suppressor kinase 1 and 2 (LATS1/2) robustly repressed LXRα activity. In the nucleus, YAP disrupted heterodimerization of LXRα with Retinoid X receptor alpha (RXRα) independently of their transcriptional activity. Consistently, hepatocyte‐specific ablation of Yap/Taz facilitated hepatic cholesterol efflux and delayed cholesterol‐induced fibrosis progression in mice. Transcriptomic analysis of MASLD patient livers confirmed a strong inverse correlation between LXRα target gene expression and liver stiffness as well as YAP/TAZ activity. These findings reveal the mechanosensitive regulation of hepatic cholesterol levels in MASLD, suggesting liver stiffness as a causal factor for hepatocyte dysfunction.