FOXA3 induction under endoplasmic reticulum stress contributes to non-alcoholic fatty liver disease.

Abstract Background & Aims Chronic ER stress in liver have been shown to play a causative role in NAFLD progression, yet the underlying molecular mechanisms remain to be elucidated. Forkhead box A3 (FOXA3), a members of FOX family, plays critical roles in metabolic homeostasis, while its possible functions in ER stress and fatty liver progression are unknown. Methods FOXA3 gain- and loss-of-function animal models were achieved via adenoviral delivery, siRNA delivery or genetic knockout mice. Tunicamycin (TM) and high-fat-diet (HFD) were administrated in mice to induce acute or chronic ER stress. ChIP-seq, luciferase assay and adenoviral-mediated downstream gene manipulations were performed to reveal the transcriptional axis involved. Key axis protein levels in livers from healthy donors and NAFLD patients were assessed via immunohistochemical staining. Results FOXA3 transcription is specifically induced by XBP1s upon ER stress. FOXA3 exacerbates the excessive lipid accumulation caused by acute ER-inducer TM, while FOXA3 deficiency in hepatocytes and mice alleviates it. Importantly, FOXA3 deficiency in mice reduced diet-induced chronic ER stress, fatty liver and insulin resistance. In addition, FOXA3 suppression via siRNA or AAV delivery treated fatty liver phenotype in HFD-induced obese mice and in db/db mice. Mechanistically, ChIP-Seq analysis revealed that FOXA3 directly regulates Period1 (Per1) transcription, which in turn promotes the expression of lipogenic genes including Srebp1c to enhance lipid synthesis. Of pathophysiological significance, FOXA3, PER1 and SREBP1c levels were increased in livers of obese mice and NAFLD patients. Conclusion The present study identified FOXA3 as the bridging molecule that links ER stress and NAFLD progression. Our results highlighted the XBP1s-FOXA3-PER1/Srebp1c transcriptional axis in the development of NAFLD and provided FOXA3 as a potential therapeutic target for fatty liver disease.