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

ABSTRACT: 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 hepatocyte-expressed 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 fenofibrate-promoted 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.

SUBMITTER: Fan S

PROVIDER: S-EPMC11252459 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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

Fan Shicheng S Gao Yue Y Zhao Pengfei P Xie Guomin G Zhou Yanying Y Yang Xiao X Li Xuan X Zhang Shuaishuai S Gonzalez Frank J FJ Qu Aijuan A Huang Min M Bi Huichang H

Acta pharmaceutica Sinica. B 20240326 7

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 hepatocyte ...[more]

PMID: 39027236

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Project description:Background and aimsPeroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear.Approach and resultsIn this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Pparafl/fl mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (PparaΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in adeno-associated virus-Yap short hairpin RNA-treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area.ConclusionsThis study revealed a function of PPARα in regulating liver size and liver regeneration through activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.

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

Publications

Fenofibrate-promoted hepatomegaly and liver regeneration are PPAR<i>α</i>-dependent and partially related to the YAP pathway.

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Dataset Information

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

Publications

Fenofibrate-promoted hepatomegaly and liver regeneration are PPAR&lt;i&gt;α&lt;/i&gt;-dependent and partially related to the YAP pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Fenofibrate-promoted hepatomegaly and liver regeneration are PPAR<i>α</i>-dependent and partially related to the YAP pathway.