Peroxisome proliferator‑activated receptor α regulates acesulfame‑K‑induced NAFLD via hepatic PLCβ: Foe and friend

Food additive acesulfame‑K (AK), a non‑nutritive sweetener, is widely used as a low‑calorie sugar substitute to reduce energy intake. However, its potential impact on nonalcoholic fatty liver disease (NAFLD) and the involvement of peroxisome proliferator‑activated receptor α (PPARα) remain unclear. In the present study, male wild‑type (WT) and PPARα‑null (KO) mice fed a 60% high‑fat diet were treated with AK (2 mg/ml) in drinking water for 12 weeks to evaluate the effects of chronic AK exposure on NAFLD progression and the role of PPARα. PPARα inhibition and activation strategies were further applied in <i>in vivo</i> and <i>in vitro</i> models to validate the key findings. AK supplementation markedly increased hepatic lipid accumulation and impaired glucose tolerance through activation of phospholipase C beta (PLCβ) in hepatic sweet taste receptor (STR) signaling in the WT mice, but not in the KO mice. Consistently, PLCβ activation was observed in AK‑induced lipid accumulation in Hepa1‑6 and Huh‑7 cells and was abolished by PPARα knockdown or inhibition. Pharmacological activation of PPARα mitigated AK‑induced NAFLD progression by suppressing PLCβ activation in STR signaling. These findings demonstrated that chronic AK intake exacerbates NAFLD progression via PLCβ activation in hepatic STR signaling and that PLCβ activation depends on physiological PPARα activity. Pharmacological PPARα activation exerts a protective effect, highlighting the dual roles of PPARα in regulating AK‑associated NAFLD risk.