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 (CCL(4)) 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 CCl(4). 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 CCl(4) and a high-fat diet.