TY - JOUR
T1 - YAP-TEAD mediates PPAR α–induced hepatomegaly and liver regeneration in mice
AU - Fan, Shicheng
AU - Gao, Yue
AU - Qu, Aijuan
AU - Jiang, Yiming
AU - Li, Hua
AU - Xie, Guomin
AU - Yao, Xinpeng
AU - Yang, Xiao
AU - Zhu, Shuguang
AU - Yagai, Tomoki
AU - Tian, Jianing
AU - Wang, Ruimin
AU - Gonzalez, Frank J.
AU - Huang, Min
AU - Bi, Huichang
N1 - Funding Information:
Supported by the Natural Science Foundation of China (82025034, 81973392, 81730103, 82020108031); the National Key Research and Development Program (2017YFE0109900); the Shenzhen Science and Technology Program (KQTD20190929174023858); the 111 Project (B16047); the Key Laboratory Foundation of Guangdong Province (2017B030314030); the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093); and the National Engineering and Technology Research Center for New Drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004) Ppara ΔHep Ppara Yap ΔHep Yap
Publisher Copyright:
© 2021 American Association for the Study of Liver Diseases.
PY - 2022/1
Y1 - 2022/1
N2 - Background and Aims: Peroxisome proliferator–activated receptor α (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. Approach and Results: 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 Ppara-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 (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 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 adeno-associated virus–Yap short hairpin RNA–treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Conclusions: This study revealed a function of PPARα 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 PPARα and suggest its potential for manipulation of liver size and liver regeneration.
AB - Background and Aims: Peroxisome proliferator–activated receptor α (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. Approach and Results: 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 Ppara-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 (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 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 adeno-associated virus–Yap short hairpin RNA–treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Conclusions: This study revealed a function of PPARα 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 PPARα and suggest its potential for manipulation of liver size and liver regeneration.
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U2 - 10.1002/hep.32105
DO - 10.1002/hep.32105
M3 - Article
C2 - 34387904
AN - SCOPUS:85121336022
SN - 0270-9139
VL - 75
SP - 74
EP - 88
JO - Hepatology
JF - Hepatology
IS - 1
ER -