YAP‐TEAD mediates peroxisome proliferator‐activated receptor α‐ induced hepatomegaly and liver regeneration in mice

Abstract

Peroxisome proliferator-activated receptor a (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically-modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly in wild-type mice and Pparafl/fl mice, while this effect was abolished in hepatocyte-specific PPARα-deficient (PparaΔHep) mice. Furthermore, PPARα agonist accelerated liver regeneration after 70% partial hepatectomy (PHx). PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area in wild-type, Pparafl/fl and PHx mice. Mechanistically, PPARα activation regulated expressions of yes-associated protein (YAP) and its downstream targets (CTGF, CYR61 and ANKRD1) as well as proliferation-related proteins (CCNA1, CCND1 and CCNE1). PPARα potentially interacted with YAP and PPARα activation induced nuclear translocation of YAP. In addition, PPARα failed to induce hepatomegaly in liver-specific YAP-deficient (Yap-/-) mice and AAV-Yap shRNA-treated mice. Blockade of YAP abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Additionally, disruption of YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly, as well as hepatocyte enlargement and proliferation. This study revealed a novel function of PPARα in regulating liver size and liver regeneration via activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.