Li Huilin, Zhou Yanying, Cai Chenghui, Liang Hangfei, Li Xuan, Huang Min, Fan Shicheng, Bi Huichang
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
Chem Biol Interact. 2025 Jan 5;405:111286. doi: 10.1016/j.cbi.2024.111286. Epub 2024 Oct 21.
Fenofibrate is a clinically prescribed drug for treating hypertriglyceridemia, which is also a classic peroxisome proliferator-activated receptor α (PPARα) agonist. We previously reported that fenofibrate induced liver enlargement in adult mice partially through activation of the yes-associated protein (YAP) signaling pathway. However, the effects of fenofibrate on liver enlargement and the YAP signaling pathway in aging mice remain unclear. In this study, D-galactose-induced aging mice, naturally aging mice, and senescence-accelerated mice P8 (SAMP8) were used to investigate the effects of aging on fenofibrate-induced liver enlargement and YAP signaling activation. The results showed that fenofibrate-induced liver enlargement in aging mice was consistent with that of adult mice. The effects of fenofibrate on hepatocyte enlargement around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area were comparable between adult and aging mice. There was no significant difference in the upregulation of PPARα downstream proteins between the two groups following fenofibrate treatment. Fenofibrate treatment also increased the expression of proliferation-related proteins and activated the YAP signaling pathway to a similar degree in both groups. In summary, these results demonstrate that the fenofibrate-induced liver enlargement and activation of the YAP pathway are consistent between adult and aging mice, indicating that the effects of fenofibrate on promoting liver enlargement and its activation of the PPARα and YAP pathway were independent of aging. These findings offer a new perspective for the clinical use of fenofibrate in elderly patients and provide a new insight for the role of PPARα in liver enlargement.
非诺贝特是一种临床上用于治疗高甘油三酯血症的药物，也是一种经典的过氧化物酶体增殖物激活受体α（PPARα）激动剂。我们之前报道过非诺贝特在成年小鼠中部分通过激活Yes相关蛋白（YAP）信号通路诱导肝脏肿大。然而，非诺贝特对衰老小鼠肝脏肿大和YAP信号通路的影响仍不清楚。在本研究中，使用D-半乳糖诱导的衰老小鼠、自然衰老小鼠和衰老加速小鼠P8（SAMP8）来研究衰老对非诺贝特诱导的肝脏肿大和YAP信号激活的影响。结果表明，非诺贝特在衰老小鼠中诱导的肝脏肿大与成年小鼠一致。非诺贝特对中央静脉（CV）区域周围肝细胞肿大和门静脉（PV）区域周围肝细胞增殖的影响在成年和衰老小鼠之间相当。非诺贝特治疗后两组PPARα下游蛋白的上调没有显著差异。非诺贝特治疗在两组中也以相似程度增加了增殖相关蛋白的表达并激活了YAP信号通路。总之，这些结果表明非诺贝特诱导肝脏肿大和YAP通路激活在成年和衰老小鼠中是一致的，表明非诺贝特促进肝脏肿大及其对PPARα和YAP通路的激活作用与衰老无关。这些发现为非诺贝特在老年患者中的临床应用提供了新的视角，并为PPARα在肝脏肿大中的作用提供了新的见解。
