Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway

Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is widely prescribed for hyperlipidemia management.Recent studies also showed that it has therapeutic potential in various liver diseases.However,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear.Here,the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,which was dependent on hepatocyteexpressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver growth and regeneration.We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination,promoting its K63-linked ubiquitination,and enhancing the interaction and transcriptional activity of the YAP-TEAD complex.Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly.Other factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver regeneration.These studies demonstrate that fenofibratepromoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

Herbal drug discovery for the treatment of nonalcoholic fatty liver disease

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease(NAFLD)and its progressive stage,nonalcoholic steatohepatitis(NASH).Traditional herbal medicines(THM)have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and mechanisms.In modern times,NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and progression.THM have garnered increased attention for providing therapeutic candidates for treating NAFLD.In this review,a new model called"multiple organs-multiple hits"is proposed to explain mechanisms of NASH progression.Against this proposed model,the effects and mechanisms of the frequentlystudied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed,among which silymarin and berberine are already under U.S.FDA-sanctioned phase 4 clinical studies.Furthermore,experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are discussed.The opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are highlighted.Increasing mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.

Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation

The constitutive androstane receptor(CAR, NR3 I1) belongs to nuclear receptor superfamily.It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein(YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver regeneration.TCPOBOP-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wildtype(WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy(PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice.Hepatocytes enlargement around central vein(CV) area was observed, meanwhile hepatocytesproliferation was promoted as evidenced by the increased number of KI67+cells around portal vein(PV)area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential proteineprotein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient(Yape/e) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.

LC–MS-based metabolomics in profiling of drug metabolism and bioactivation

Since metabolism significantly affects drug safety and efficacy,determining the metabolic profile of a drug is a critical part of drug development.The application of an LC–MS-based metabolomic approach has gained more widespread use in identifying drug metabolites,developing metabolic maps and lending clues to mechanisms of bioactivation.Thus,the LC–MS-based metabolomic approach is a powerful tool for profiling of drug metabolism and bioactivation.