Hepatocyte-Specific Yap1 Knockout Maintained the Liver Homeostasis of Lipid Metabolism in Mice.

Introduction: Yes-associated protein 1 (YAP1) is a crucial molecule in the Hippo pathway. The impact of hepatocyte-specific Yap1 knockout (Yap1^LKO) on hepatic lipid droplets (LD) and pePLIN2 in metabolic fatty liver has not been reported. This study aims to explore whether Yap1^LKO could offer a protective effect in a liver injury model. Methods: Three-week-old Yap1^LKO and Yap1^Flox mice were given aristolochic acid I (AAI) combined carbon tetrachloride (CCL₄) establish liver injury model. Eight-week-old Yap1^LKO and Yap1^Flox mice were fed with a high-fat diet for 18 weeks to establish obesity-related liver injury model. Further biochemical, histomorphological, immunohistochemical, and lipidomic analyses were performed on serum and liver tissues of these mice to elucidate the effects of hepatocyte-specific Yap1 knockout on hepatic lipid metabolism. Results: Yap1^LKO reduced triglyceride (TG) content and PLIN2 expression level in the liver during the intervention of AAI combined CCl₄. Moreover, Yap1^LKO improved lipid metabolism homeostasis in the liver by increasing the beneficial lipid molecules and reducing the harmful lipid molecules through lipidomics. Finally, Yap1^LKO reduced TG content in the serum and liver, hepatic vacuolar degeneration, and hepatic PLIN2 expression level in mice fed with a high-fat diet (HFD). Conclusion: Yap1^LKO is protective in regulating liver and blood TG when induced with toxic substances AAI combined CCl₄ and a high-fat diet. [ABSTRACT FROM AUTHOR]