Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China.
Department of Cellular Biology, Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, 601 Huangpu Ave. West, Guangzhou 510632, Guangdong Province, China.
Mol Metab. 2022 Nov;65:101584. doi: 10.1016/j.molmet.2022.101584. Epub 2022 Aug 30.
Pituitary adenylate cyclase-activating polypeptide (PACAP) was reported to attenuate hepatic lipid accumulation in overnutrition-related metabolic disorder, mediated by up-regulation of fas apoptosis inhibitory molecule (FAIM). However, how PACAP regulates FAIM in metabolic tissues remains to be addressed. Here we investigated the underlying mechanism on the role of PACAP in ameliorating metabolic disorder and examined the potential therapeutic effects of PACAP in preventing the progression of metabolic associated fatty liver disease (MAFLD).
Mouse models with MAFLD induced by high-fat diet were employed. Different doses of PACAP were intraperitoneally administrated. Western blot, luciferase assay, lentiviral-mediated gene manipulations and animal metabolic phenotyping analysis were performed to explore the signaling pathway involved in PACAP function.
PACAP ameliorated the excessive hepatic lipid accumulation and inhibited lipogenesis in HFD-fed C57BL/6J mice. Mechanistically, PACAP activated the FAIM-AMPK-IRβ axis to inhibit the expression of lipid synthesis genes, and FAIM mediated the effects of PACAP. FAIM suppression via lentiviral-mediated shRNA inhibited the activation of AMPK, whereas FAIM overexpression promoted AMPK activation. PACAP increased the promoter activity of FAIM gene through activating PKA-CREB signaling pathway.
Our work demonstrated that the administration of PACAP represented a feasible approach for treating hepatic lipid accumulation in MAFLD. The findings reveal the molecular mechanism that PACAP increase FAIM expression and activates the FAIM/AMPK/IRβ signaling axis, thus inhibits lipogenesis to mediate its beneficial effects.
有研究报道，垂体腺苷酸环化酶激活肽（PACAP）可通过上调 Fas 凋亡抑制分子（FAIM）来减轻与营养过剩相关的代谢紊乱中的肝脂质积累。然而，PACAP 如何在代谢组织中调节 FAIM 仍有待研究。本研究旨在探讨 PACAP 在改善代谢紊乱中的作用机制，并研究 PACAP 预防代谢相关脂肪性肝病（MAFLD）进展的潜在治疗作用。
采用高脂肪饮食诱导的 MAFLD 小鼠模型，腹腔内给予不同剂量的 PACAP。通过 Western blot、荧光素酶检测、慢病毒介导的基因操作和动物代谢表型分析等方法，探讨参与 PACAP 功能的信号通路。
PACAP 改善了 HFD 喂养的 C57BL/6J 小鼠的肝脂质过度积累并抑制了脂肪生成。机制上，PACAP 通过激活 FAIM-AMPK-IRβ 轴来抑制脂质合成基因的表达，FAIM 介导了 PACAP 的作用。通过慢病毒介导的 shRNA 抑制 FAIM 表达可抑制 AMPK 的激活，而 FAIM 过表达则促进 AMPK 的激活。PACAP 通过激活 PKA-CREB 信号通路增加 FAIM 基因的启动子活性。
本研究表明，PACAP 的给药为治疗 MAFLD 中的肝脂质积累提供了一种可行的方法。研究结果揭示了 PACAP 增加 FAIM 表达并激活 FAIM/AMPK/IRβ 信号通路，从而抑制脂肪生成来介导其有益作用的分子机制。
