PACAP attenuates hepatic lipid accumulation through the FAIM/AMPK/IRβ axis during overnutrition

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. [Display omitted] •PACAP ameliorates hepatic lipid accumulation through the AMPK pathway.•AMPK is a downstream mediator of FAIM.•FAIM is transcriptionally activated by CREB and regulated by PACAP.•PACAP regulates the FAIM-AMPK-IRβ axis to treat fatty liver phenotype.