Source: School of Pharmaceutical Sciences
Edited by: Tan Rongyu, Wang Dongmei
Recently, Prof. Huichang Bi’s group from School of Pharmaceutical Sciences, Sun Yat-sen University published a research article entitled “YAP-TEAD mediates peroxisome proliferator-activated receptor α-induced hepatomegaly and liver regeneration in mice” in the
Hepatology. This work revealed a novel function of PPARα in regulating liver size and liver regeneration via activation of the YAP-TEAD signaling pathway, provides clinical implications for understanding the physiological functions of PPARα, and suggests its potential for manipulation of liver size and liver regeneration.
PPARα 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 and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and
Pparafl/fl mice, while these effects were abolished in hepatocyte-specific
Pparα-deficient (
PparaΔHep) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (CTGF, CYR61 and ANKRD1) as well as proliferation-related proteins (CCNA1, CCND1 and CCNE1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly, and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in AAV-Yap shRNA-treated mice and liver-specific
Yap-deficient (
YapΔHep) mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area, suggesting that PPARα-induced hepatomegaly is YAP-dependent.
In summary, this work demonstrated that PPARα induces hepatomegaly and liver regeneration by increasing cell size around the CV area and promoting hepatocyte proliferation around the PV area. The E domain of PPARα is critical for the PPARα-YAP interaction. Furthermore, activation of the YAP-TEAD signaling pathway is the key mechanism in PPARα-induced liver enlargement and regeneration. These results have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration. These findings also provide a clinically relevant approach for using PPARα as a therapeutic target for promoting hepatic regenerative process and liver repair.
The first authors of this paper are Shicheng Fan, Yue Gao from School of Pharmaceutical Sciences. The corresponding author is Prof. Huichang Bi from School of Pharmaceutical Sciences. The work was supported by the grant from the National Natural Science Foundation of China.
Link to the article:
https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32105
