PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish.
PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish.
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在斑马鱼中，PPARα的激活通过抑制YAP信号来促进肝祖细胞介导的肝再生。
DOI：
10.1038/s41598-023-44935-5
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发表时间：
2023-10-25
影响因子：
4.6
通讯作者：
Shin, Donghun
中科院分区：
文献类型：
--
作者：
Kim, Minwook;So, Juhoon;Shin, Donghun
尽管肝脏具有强大的再生能力，但长期和严重的肝损伤会损害肝脏再生，导致肝功能衰竭。由于肝脏可将肝祖细胞（LPC）分化为肝细胞以恢复功能性肝细胞，因此增强LPC介导的肝再生可能对慢性肝病患者有益。然而，LPC向肝细胞分化的分子机制仍不清楚。使用LPC介导的肝再生的斑马鱼模型Tg（fabp 10a：pt-β-catenin），我们提出过氧化物酶体增殖物激活受体α（PPARα）激活增强LPC向肝细胞的分化。我们发现，用GW 7647（一种有效的PPARα激动剂）处理Tg（fabp 10a：pt-β-catenin）幼虫，可增强肝细胞标志物的表达，同时降低再生肝脏中胆管上皮细胞（BEC）/LPC标志物的表达，表明增强了LPC向肝细胞的分化。从机制上讲，PPARα激活通过抑制雅普信号传导增强分化。GW 7647处理导致的分化表型通过表达组成型活性形式的Yap 1而被拯救。此外，我们发现抑制雅普信号传导足以促进LPC向肝细胞分化。用抑制雅普信号传导的TEAD抑制剂K-975处理Tg（fabp 10 a：pt-β-catenin）幼虫，表型模拟了GW 7647对LPC分化的影响。总之，我们的研究结果为增强LPC介导的肝再生作为慢性肝病的再生疗法提供了见解。
Despite the robust regenerative capacity of the liver, prolonged and severe liver damage impairs liver regeneration, leading to liver failure. Since the liver co-opts the differentiation of liver progenitor cells (LPCs) into hepatocytes to restore functional hepatocytes, augmenting LPC-mediated liver regeneration may be beneficial to patients with chronic liver diseases. However, the molecular mechanisms underlying LPC-to-hepatocyte differentiation have remained largely unknown. Using the zebrafish model of LPC-mediated liver regeneration, Tg(fabp10a:pt-β-catenin), we present that peroxisome proliferator-activated receptor-alpha (PPARα) activation augments LPC-to-hepatocyte differentiation. We found that treating Tg(fabp10a:pt-β-catenin) larvae with GW7647, a potent PPARα agonist, enhanced the expression of hepatocyte markers and simultaneously reduced the expression of biliary epithelial cell (BEC)/LPC markers in the regenerating livers, indicating enhanced LPC-to-hepatocyte differentiation. Mechanistically, PPARα activation augments the differentiation by suppressing YAP signaling. The differentiation phenotypes resulting from GW7647 treatment were rescued by expressing a constitutively active form of Yap1. Moreover, we found that suppression of YAP signaling was sufficient to promote LPC-to-hepatocyte differentiation. Treating Tg(fabp10a:pt-β-catenin) larvae with the TEAD inhibitor K-975, which suppresses YAP signaling, phenocopied the effect of GW7647 on LPC differentiation. Altogether, our findings provide insights into augmenting LPC-mediated liver regeneration as a regenerative therapy for chronic liver diseases.
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DOI：
10.1002/stem.2283
发表时间：
2016-05
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
Jung KH;McCarthy RL;Zhou C;Uprety N;Barton MC;Beretta L
通讯作者：
Beretta L
影响因子：
4.6
作者：
Anzai K;Tsuruya K;Ida K;Kagawa T;Inagaki Y;Kamiya A
通讯作者：
Kamiya A
DOI：
10.1002/hep.32105
发表时间：
2022-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
13.5
作者：
Borude, Prachi;Edwards, Genea;Walesky, Chad;Li, Feng;Ma, Xiaochao;Kong, Bo;Guo, Grace L.;Apte, Udayan
通讯作者：
Apte, Udayan
影响因子：
16.6
作者：
Lee DH;Park JO;Kim TS;Kim SK;Kim TH;Kim MC;Park GS;Kim JH;Kuninaka S;Olson EN;Saya H;Kim SY;Lee H;Lim DS
通讯作者：
Lim DS