Tirzepatide alleviates non-alcoholic fatty liver disease by regulating lipid metabolism through activation of the AMPK/NF-κB signaling pathway.

backgroundNon-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder with limited therapeutic options. Tirzepatide (TZP), a novel dual agonist, has shown promise in metabolic disease, but its effects and mechanisms in NAFLD remain unclear.

methodsHuman HepG2 cells were treated with palmitate (PA) to induce steatosis and then exposed to various concentrations of TZP. Mouse were treated with high-fat diet (HFD) to establish a NAFLD model in vivo, followed by TZP treatment. NAFLD-related indicators including cell viability, intracellular lipid accumulation, serum biochemical parameters, glucose homeostasis, inflammation, oxidative stress, and hepatic histopathology were evaluated. The AMP-activated protein kinase (AMPK)/nuclear factor κB (NF-κB) pathway and lipid metabolism-related protein were analyzed.

resultsTZP suppressed PA-induced lipid accumulation, triglyceride and total cholesterol content, cell apoptosis, while it enhanced cell viability in HepG2 cells. In HFD-induced NAFLD mice, TZP treatment markedly decreased liver weight, attenuated hepatic steatosis, ballooning, and necrosis, and abnormal lipid accumulation by inhibiting insulin resistance, inflammatory cytokines, oxidative stress, and hepatic fibrosis markers. Mechanistically, TZP modulated the AMPK/NF-κB pathway by increasing p-AMPK and decreasing p-NF-κB levels, leading to downregulation of lipogenic genes.

conclusionTZP effectively improved hepatic steatosis, inflammation, oxidative stress, and fibrosis in experimental NAFLD models through the AMPK/NF-κB pathway.