Caveolin-1 mitigates the advancement of metabolic dysfunction-associated steatotic liver disease by reducing endoplasmic reticulum stress and pyroptosis through the restoration of cholesterol homeostasis.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, which has the potential to advance to fibrosis. CAV1 has the effects of improving liver lipid deposition in MASLD, however, the potential mechanism is largely unknown. Here, we establish a MASLD mouse model in CAV1 knockout (KO) mice and perform transcriptome analysis on livers from mice to investigate the effects of CAV1 in MASLD progression. In addition, we evaluated the expression of CAV1 in human liver samples, and also conducted assaysto investigate the molecular role of CAV1 in MASLD progression. The results illustrate that the expression of liver CAV1 in the decreases during MASLD progression, which aggravates the accumulation of cholesterol in the liver, leading to more severe endoplasmic reticulum (ER) stress and pyroptosis. Mechanistically, CAV1 regulates the expression of FXR/NR1H4 and its downstream cholesterol transporter, ABCG5/ABCG8, suppressing ER stress and alleviating pyroptosis. Our study confirms CAV1 is a crucial regulator of cholesterol homeostasis in MASLD and plays an important role in disease progression.