ࡱ> RTQO R, bjbj;;8&QWiQWi\\\\\ppp8pC~ "B NwByByByByByByB$EPH\B9\V  VVB\\HBV\\ApVwB,. ЪF-@B0C-HZFH(..H\/7 VVVVVVVBBVVVCVVVVHVVVVVVVVVb ": DN1 Xd!jgFenofibrate induced-hepatomegaly and liver regeneration is PPAR- dependent and partially related to the activation of YAP pathwayShicheng Fan1, Yue Gao2, Min Huang2*, Huichang Bi1*1 School of Pharmaceutical Sciences, Southern Medical University2 School of Pharmaceutical Sciences, Sun Yat-sen UniversityFenofibrate, an agonist of peroxisome proliferator-activated receptor  (PPAR), has been widely used as a lipid-regulating agent in clinical practice. Recent studies found that fenofibrate treatment induced hepatomegaly in mice, but the mechanisms involved remain unclear. YAP, the key effector of Hippo signaling pathway, plays an important role in manipulating the liver size and regeneration. The aim of this study is to identify the role of YAP in fenofibrate-induced hepatomegaly and liver regeneration. The effects of fenofibrate on liver enlargement and liver regeneration were investigated in wild-type, Pparafl/fl, and hepatocyte-specific Ppara-deficient (PparaHep) mice. The results showed that administration of fenofibrate significantly induced liver enlargement and promoted liver regeneration after partial hepatectomy, accompanied by hepatocyte hypertrophy around the central vein area and enhanced hepatocyte proliferation around the portal  " 8 : L N d f h  Ͻppp^p^Hp+hK9)h2.B*CJH*OJQJaJo(ph"h2.B*CJH*OJQJaJph(hK9)h2.B*CJH*OJQJaJphh2.B*CJOJQJaJph"h2.B*CJOJQJaJo(ph+hIh2.5B*CJOJQJ\aJph#hJh2.5CJKHOJQJaJ h2.5CJKHOJQJaJo(&hJh2.5CJKHOJQJaJo(h !$5B*aJph     gd_! d\7$8$gd2.gd2.$a$gd2. $dha$gd2.$a$gd2.gd !$                " ʺ~~~~zvzvzvzvzhnhBhuh\Zjh\ZUh2.h !$5B*aJph hh2. h2.o()h2.5B*CJKHOJQJaJo(phhp~Rh2.CJOJQJaJo(h2.5CJOJQJ\aJo(h2.B*CJOJQJaJphU%hIh2.B*CJOJQJaJph. vein area. Mechanistically, fenofibrate regulated the expressions of YAP and its downstream targets. Fenofibrate activated YAP signaling via suppressing K48-linked ubiquitination and promoting K63-linked ubiquitination, and enhancing interaction and transcriptional activity of YAP-TEAD complex. Suppression of YAP using AAV-Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly, as well as hepatocyte hypertrophy and proliferation. Other factors might also participate in fenofibrate-induced hepatomegaly, including MYC, KRT23, RHOA, and RAS. These studies revealed a novel role of fenofibrate in promoting liver enlargement and regeneration partially through activating the YAP signaling pathway. These findings provide clinical implications of fenofibrate as a potential medication for promoting liver regeneration following PHx. Key WordsFenofibrate; peroxisome proliferator-activated receptor a; hepatomegaly; liver regeneration; yes-associated proteinb?zXdSlingnanDMPK2023@163.com:         " $ & ( * , gd !$&dPgdBhu" $ & ( * , h2.h !$5B*aJphhBhuhn6182P:p[. 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