Astaxanthin ameliorates early steatohepatitis in high-fat diet-fed mice via SREBP1c downregulation and oxidative stress suppression

Purpose This study aims to investigate the protective effects and underlying mechanisms of astaxanthin (AST), a potent natural carotenoid, against high-fat diet (HFD)-induced steatohepatitis, a key stage in nonalcoholic fatty liver disease (NAFLD). Design/methodology/approach Male C57BL/6 mice were fed a normal diet (ND) or a 60% HFD for 6 weeks. HFD-fed mice were further divided into groups receiving either a vehicle or AST supplementation at 50 or 150 mg/kg/day via oral gavage. Systemic metabolic parameters (body composition, insulin resistance, lipid profiles, adipokines), hepatic steatosis (histology, lipid content), oxidative stress markers including reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (T-AOC), inflammation including tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), phosphorylated nuclear factor-kappa B p65 (p-NF-κB p65) and the expression of key lipogenic genes (Srebp1c, Fasn, Acaca, Scd1, Hmgcr) were analyzed. Findings AST supplementation dose-dependently attenuated HFD-induced systemic metabolic disturbances, including obesity, adipokine imbalance (normalized leptin/adiponectin ratio), insulin resistance (reduced HOMA-IR) and dyslipidemia. In the liver, AST markedly alleviated steatosis, oxidative stress and pro-inflammatory cytokine production. Mechanistically, these benefits were associated with the downregulation of the master lipogenic transcription factor sterol regulatory element-binding protein 1c (SREBP1c) and its downstream target genes (Fasn, Acaca, Scd1), thereby suppressing de novo lipogenesis. Originality/value This study provides the evidence that AST protects against HFD-induced early steatohepatitis through a coordinated mechanism involving the transcriptional repression of SREBP1c to concurrently inhibit hepatic lipogenesis and mitigate oxidative stress. This dual-pathway intervention highlights the value of AST as a multi-targeting modulator for managing diet-induced NAFLD.