Liraglutide inhibits receptor for advanced glycation end products (RAGE)/reduced form of nicotinamide-adenine dinucleotide phosphate (NAPDH) signaling to ameliorate non-alcoholic fatty liver disease (NAFLD) in vivo and vitro

Abstract

ABSTRACT The study was designed to investigate the effects of liraglutide and reveal its action mechanism associated with RAGE/NAPDH in NAFLD. The liver tissue was collected for HE, Masson, and ROS staining. Apoptosis levels were detected through TUNEL staining and ROS levels were evaluated through ROS staining. The expression levels of c-Jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β) were detected through Western blot. JNK and the expression of Collagenα1, Collagenα2 and connective tissue growth factor (CTGF) were detected through RT-qPCR and Western blot and the expression in mouse liver stellate cells (JS-1) cells were evaluated through immunofluorescence staining. We detected the effects of liraglutide on NAFLD in high-fat diet (HFD)-fed mice. Liraglutide treatment improved bridging fibrosis and liver function, as well as lessening ROS levels and the protein levels of RAGE, NOX1, NOX2 and NOX4. In PA and H2O2-induced AML12 cells, liraglutide treatment was able to decrease cell apoptosis, ROS levels and the levels of inflammatory factors including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, while it effects were reversed by the induction of RAGE overexpression or NOX2 overexpression. In JS-1 cells treated with medium culturing AML12 cells, liraglutide markedly suppressed cell proliferation and activation, while RAGE overexpression or NOX2 overexpression blunted these effects of liraglutide. Taken together, liraglutide exerts a protective role in improving liver injury caused by HFD, which could be related to decreased apoptosis and oxidative stress of liver cells, as well as decreased proliferation and activation of hepatic stellate cells through RAGE/NOX2.