Type 2 diabetes (T2DM) is closely associated with hepatic injury, which could promote/exacerbate hepatic
inflammation, steatosis, and accelerate
liver fibrosis progression.
Aucubin (AU), as an active ingredient isolated from Eucommia ulmoides, exists a nutritional value in hepatoprotective effect and
diabetic complications. However, whether it possesses more outstanding features on improving liver injury in diabetic conditions and the underlying mechanism is unclear. Our research investigated the treatment of AU on
liver fibrosis and potential mechanisms on high-fat diet/
streptozotocin-induced diabetic mice and high
glucose (HG)&TGF-β1-induced LX-2 cells. Results showed that AU restored hepatic function without affecting
blood sugar levels in diabetic mice. Meanwhile, the enhanced levels of total
cholesterol,
triglycerides, and
LDL-c were reversed in hepatic tissue after AU treatment. Histomorphology assays including H&E, Masson, PAS, Oil red and Sirius red staining showed that AU treatment reduced liver swelling, steatosis and
fibrosis. Mechanistic studies showed that AU alleviated NLRP3
inflammasome activation and inflammatory responses via inhibiting ER stress-mediated IRE1α/TXNIP signaling pathway, which could postpone the development of T2DM induced hepatic
fibrosis. In addition, the ROS generation and the up-regulated expression of
NADHP oxidase 4 (NOX4) in the liver tissue were suppressed by AU treatment. Moreover, in vitro model, NOX4 activation was prominently enhanced and AU treatment blocked HG&TGF-β1-induced NOX4 derived
superoxide generation and thereby ameliorating hepatic stellate cell activation, which can be abrogated in the overexpression of NOX4 LX-2 cells. In addition, inhibition effects on ER stress-mediated IRE1α/TXNIP/NLRP3
inflammasome by AU treatment also were abolished in the overexpression of NOX4 LX-2 cells. Meanwhile, molecular docking results indicated that AU and
NOX4 protein have a higher affinity. Taken together, AU might be a potential nutraceutical or therapeutic
drug to ameliorate hepatic impairment and
fibrosis in T2DM.