Fenofibrate induced‐hepatomegaly and liver regeneration is PPARα dependent and partially related to the activation of YAP pathway

Abstract

Background and ObjectiveFenofibrate, 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.MethodsThe effect of fenofibrate on hepatomegaly and liver regeneration was investigated in several strains of genetically‐modified mice including Pparafl/fland 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.ResultsThe 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.ConclusionThese 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.