Tirzepatide alleviates non-alcoholic fatty liver disease by regulating lipid metabolism through activation of the AMPK/NF-κB signaling pathway. | Pepdox
Tirzepatide alleviates non-alcoholic fatty liver disease by regulating lipid metabolism through activation of the AMPK/NF-κB signaling pathway.
American journal of translational research2025PMID: 41552345
In vitro and in vivo study examining tirzepatide's effects on non-alcoholic fatty liver disease through AMPK/NF-κB signaling pathway activation. HepG2 cells and HFD mice treated with tirzepatide showed reduced lipid accumulation, inflammation, and steatosis through AMPK activation and NF-κB inhibition. Identifies the AMPK/NF-κB pathway as a key hepatic mechanism for tirzepatide's MASLD benefits—explaining how dual GIP/GLP-1 agonism achieves liver-specific anti-inflammatory and lipid metabolism effects beyond what would be expected from weight reduction alone.
Abstract
BACKGROUND: Non-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.
METHODS: Human 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.
RESULTS: TZP 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.
CONCLUSION: TZP effectively improved hepatic steatosis, inflammation, oxidative stress, and fibrosis in experimental NAFLD models through the AMPK/NF-κB pathway.