YAP-TEAD mediates PPAR α-induced hepatomegaly and liver regeneration in mice.
YAP-TEAD mediates PPAR α-induced hepatomegaly and liver regeneration in mice.
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DOI：
10.1002/hep.32105
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发表时间：
2022-01
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影响因子：
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过氧化物酶体增殖物激活受体α（Peroxisome proliferator-activated receptor α，PPARα，NR 1C 1）是一种配体激活的核受体，参与脂质代谢和能量稳态的调节。过氧化物酶体增殖物激活受体α激活诱导肝肿大，并在肝再生中发挥重要作用，但其潜在机制尚不清楚。在这项研究中，在几种转基因小鼠中研究了PPARα激活对肝脏增大和再生的影响。在野生型小鼠和Pparafl/fl小鼠中，特异性激动剂WY-14643激活的PPARα可显著诱导肝肿大，并加速70%部分肝切除术（PHx）后的肝再生，而在肝细胞特异性Ppara缺陷（PparaΔHep）小鼠中，这些作用消失。此外，激活的PPARα促进肝细胞肥大周围的中央静脉区域和肝细胞增殖周围的门静脉区域。从机制上讲，PPARα激活调节yes相关蛋白（雅普）及其下游靶点（结缔组织生长因子、富含半胱氨酸的血管生成诱导物61和锚蛋白重复结构域1）以及增殖相关蛋白（细胞周期蛋白A1、D1和E1）的表达。雅普与PPARα E结构域的结合是雅普与PPARα相互作用的关键。PPARα激活进一步诱导雅普核转位。破坏YAP-转录增强因子结构域家族成员（TEAD）的关联可显著抑制PPARα诱导的肝肿大以及肝细胞增大和增殖。此外，在腺相关病毒-Yap短发夹RNA处理的小鼠和肝脏特异性Yap缺陷小鼠中，PPARα未能诱导肝肿大。阻断雅普信号通路可抑制PPARα诱导的中央静脉区肝细胞肥大和门静脉区肝细胞增殖。该研究揭示了PPARα通过激活YAP-TEAD信号通路调节肝脏大小和肝再生的功能。这些发现对于理解PPARα的生理功能具有意义，并表明其在操纵肝脏大小和肝脏再生方面的潜力。
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. 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. 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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影响因子：
21.3
作者：
Cox AG;Hwang KL;Brown KK;Evason K;Beltz S;Tsomides A;O'Connor K;Galli GG;Yimlamai D;Chhangawala S;Yuan M;Lien EC;Wucherpfennig J;Nissim S;Minami A;Cohen DE;Camargo FD;Asara JM;Houvras Y;Stainier DYR;Goessling W
通讯作者：
Goessling W
影响因子：
4.5
作者：
Gonzalez, Frank J.;Shah, Yatrik A.
通讯作者：
Shah, Yatrik A.
影响因子：
12.8
作者：
Lu L;Finegold MJ;Johnson RL
通讯作者：
Johnson RL
影响因子：
11.2
作者：
Cheung, C;Akiyama, TE;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
角蛋白 23 是一种过氧化物酶体增殖物激活受体 Alpha 依赖性、MYC 扩增癌基因，可促进肝细胞增殖
影响因子：
13.5
作者：
Kim, Donghwan;Brocker, Chad N.;Gonzalez, Frank J.
通讯作者：
Gonzalez, Frank J.