Low‐Dose Polystyrene Nanoplastics Alleviate High‐Fat Diet‐Induced Hepatic Injury via <scp>AMPK</scp> / <scp>mTOR</scp> ‐Mediated Lipophagy Activation

BACKGROUND: Microplastics (MPs) or nanoplastics (NPs) are emerging environmental pollutants, but current studies predominantly focus on the hepatotoxicity of high-dose MPs, whereas the health effects of low-dose MPs under high-fat diet (HFD) conditions remain unclear. We aimed to investigate the hepatotoxicity induced by combined exposure to high-fat diet and low-dose microplastics. METHODS: Male Wistar rats were administered a high-fat diet (HFD) without (HFD) or with polystyrene nanoparticles (PS-NPs) (HFD-NP) for consecutive 90 days. In vitro experiments were conducted using primary hepatocytes treated with PS-NPs and palmitic acid (PA) in the presence or absence of AMPK or an autophagy inhibitor for 24 h. RESULTS: H&E staining revealed significant lipid accumulation, inflammation, and hepatic fibrosis in livers from HFD group, whereas no obvious pathological changes were observed in NP group. Notably, these effects were greatly diminished in HFD-NP group, compared with HFD group. In vitro experiments also showed that PS-NPs displayed no apparent effect on the viability of primary hepatocytes, while significantly alleviated palmitic acid (PA)-induced hepatocyte apoptosis and lipid droplet accumulation. These observations indicate that low-dose PS-NPs mitigate hepatotoxicity induced by HFD. Furthermore, hepatic lipid oxidation and utilization were enhanced in HFD-NP rats, suggesting that PS-NPs may modulate lipid metabolism upon HFD. Transcriptomic analysis revealed the mechanism might involve the activated AMPK signalling pathway and inhibited mTOR signalling pathway, important regulators for autophagy, implying the involvement of lipophagy in this process. Furthermore, in vitro experiments showed the inhibition of lipid droplet autophagy exacerbated HFD-induced hepatotoxicity. CONCLUSION: Our results indicate low-dose PS-NPs can activate the AMPK pathway and lipophagy, thereby alleviating liver injury through a stress adaptation response under high-fat diet conditions. Our findings elucidate the context-dependent interaction between microplastics and dietary patterns in liver diseases development and provide novel insights into the health effects of microplastics.