J Hepatol: FoxA3 induces expression to promote the development of non-alcoholic fatty liver when endo-network stress occurs

Chronic endo-network stress in the liver plays an important role in the onset of non-alcoholic fatty liver disease (NAFLD), but its underlying molecular mechanism is not clear.
A3 (FOXA3) is a member of the FOX family and play an important role in metabolic stability, but its potential function in ER stress and fatty liver progression is unclear.
researchers used adenovirus vectors, siRNA vectors, or gene knock-out mice to build animal models that were obtained and missing from FOXA3 functions.
TM and high-fat diet (HFD) respectively to induce acute and chronic ER stress in mice.
use chip sequence analysis, luciferase analysis and adenovirus-mediated downstream gene operation clearly related transcription axis.
detect protein levels in key axes in the livers of healthy donors and NAFLD patients through immunosomal chemical staining.
XBP1 can specifically induce FOXA3 transcription under the condition that the excess expression of FOXA3 causes lipids to accumulate excessively in the endonet stress conditions.
FOXA3 can exacerbate excessive lipid build-up caused by acute ER inducerTM, which can be mitigated when FOXA3 is lacking in liver cells and mice.
, diet-induced chronic ER stress, fatty liver and insulin resistance were reduced in mice lacking FOXA3.
siRNA inhibits FOXA3 expression to reduce liver fat accumulation in addition, and inhibition of FOXA3 through siRNA or AAV delivery can treat fatty liver estypes in HFD-induced mice and db/db mice.
CHIP-seq analysis shows that FOXA3 directly regulates the transcription of Period1 (PER1), which in turn promotes the expression of lipid-causing genes, including Srebp1c, thus enhancing lipid synthesis.
in pathophysiological sense, the levels of FOXA3, PER1 and SREBP1c in the livers of obese mice and NAFLD patients showed elevated levels.
summary model diagram study makes it clear that FOXA3 is a bridge molecule linking ER stress and NAFLD progression, highlighting the role of XBP1s-FOXA3-PER1/Srebp1c transcription shafts in the development of NAFLD, suggesting that FOXA3 can be a potential target for fatty liver therapy.