(699.14) Fenofibrate induced-hepatomegaly and liver regeneration is PPARα dependent and partially related to the activation of YAP pathway

Poster Board Number: B127

Shicheng Fan (School of Pharmaceutical Sciences, Sun Yat-sen University), Yue Gao (School of Pharmaceutical Sciences, Sun Yat-sen University), Aijuan Qu (School of Basic Medical Sciences, Capital Medical University), Yiming Jiang (School of Pharmaceutical Sciences, Sun Yat-sen University), Guomin Xie (School of Basic Medical Sciences, Capital Medical University), Xinpeng Yao (School of Pharmaceutical Sciences, Sun Yat-sen University), Xiao Yang (School of Pharmaceutical Sciences, Sun Yat-sen University), Tomoki Yagai (Center for Cancer Research, National Institutes of Health), Jianing Tian (School of Pharmaceutical Sciences, Sun Yat-sen University), Ruimin Wang (School of Pharmaceutical Sciences, Sun Yat-sen University), Frank Gonzalez (Center for Cancer Research, National Institutes of Health), Min Huang (School of Pharmaceutical Sciences, Sun Yat-sen University), Huichang Bi (School of Pharmaceutical Sciences, Sun Yat-sen University, School of Pharmaceutical Sciences, Sun Yat-sen University)

Background and

Objective: Fenofibrate, an agonist of peroxisome proliferator activated receptor α (PPARα), has been widely used as a lipid-regulating agent in clinical practice. Recent studies found that fenofibrate can significantly induce hepatomegaly in mice, but the involved mechanisms remain unclear.

Methods: The effect of fenofibrate on hepatomegaly and liver regeneration was investigated in several strains of genetically-modified mice including Pparafl/fl and PparaΔHep mice. Staining assays were performed to investigate the effect of fenofibrate on hepatocyte size and proliferation during hepatomegaly and liver regeneration. AAV-Yap shRNA mice model was further used to determine the role of YAP in PPARα-induced hepatomegaly. Western blot analysis was used to detect the protein expressions of YAP signaling pathway as well as other factors potentially involved in fenofibrate-induced hepatomegaly.

Results: The study demonstrated that fenofibrate significantly induced liver enlargement in wild-type and Pparafl/fl mice, while this effect was abolished in hepatocyte-specific Ppara-deficient (PparaΔHep) mice. Furthermore, fenofibrate significantly promoted liver regeneration in wild-type mice following 70% partial hepatectomy (PHx). Staining assays revealed that fenofibrate promoted hepatocyte enlargement around the central vein area and hepatocyte proliferation around the portal vein area in wild-type, Pparafl/fl and PHx mice. Fenofibrate regulated protein expressions of YAP and its downstream targets (CTGF, CRY61 and ANKRD1) as well as proliferation-related proteins (CCNA1, CCND1 and CCNE1). Suppression of YAP using AAV-Yap shRNA repressed fenofibrate-induced hepatomegaly, as well as hepatocyte enlargement and proliferation. Other factors might also participate in fenofibrate-induced hepatomegaly, including MYC, KRT23, RHOA and RAS.

Conclusion: These studies revealed a novel role of fenofibrate in promoting liver enlargement and regeneration, which is PPARα dependent and partially related to the activation of YAP signaling pathway. These findings provide clinical relevance of fenofibrate as a potential medication for promoting liver regeneration.

Support or Funding Information

The work was supported by the Natural Science Foundation of China [Grant number: 82025034, 81973392, 81730103, 82020108031], the National Key Research and Development Program [Grant number: 2017YFE0109900], the Shenzhen Science and Technology Program (KQTD20190929174023858), the 111 project [Grant number: B16047], the Key Laboratory Foundation of Guangdong Province [Grant number: 2017B030314030], the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [Grant number: 2017BT01Y093], and the National Engineering and Technology Research Center for New drug Druggability Evaluation [Seed Program of Guangdong Province, Grant number: 2017B090903004].