YAP-TEAD mediates PPAR alpha-induced hepatomegaly and liver regeneration in mice

Background and Aims Peroxisome proliferator-activated receptor alpha (PPAR alpha, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPAR alpha activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. Approach and Results In this study, the effect of PPAR alpha activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPAR alpha activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Ppara(fl/fl) mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (Ppara(Delta Hep)) mice. Moreover, PPAR alpha activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPAR alpha activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPAR alpha E domain was critical for the interaction between YAP and PPAR alpha. PPAR alpha activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPAR alpha-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPAR alpha failed to induce hepatomegaly in adeno-associated virus-Yap short hairpin RNA-treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPAR alpha-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Conclusions This study revealed a function of PPAR alpha in regulating liver size and liver regeneration through activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPAR alpha and suggest its potential for manipulation of liver size and liver regeneration.