Polystyrene nanoplastics induce lipophagy via the AMPK/ULK1 pathway and block lipophagic flux leading to lipid accumulation in hepatocytes

Micro- and nanoplastic pollution has emerged as a significant global concern due to their extensive presence in the environment and potential adverse effects on human health. Nanoplastics can enter the human circulatory system and accumulate in the liver, disrupting hepatic metabolism and causing hepatotoxicity. However, the precise mechanism remains uncertain. Lipophagy is an alternative mechanism of lipid metabolism involving autophagy. This study aims to explore how polystyrene nanoplastics (PSNPs) influence lipid metabolism in hepatocytes via lipophagy. Initially, it was found that PSNPs were internalized by human hepatocytes, resulting in decreased cell viability. PSNPs were found to induce the accumulation of lipid droplets (LDs), with autophagy inhibition exacerbating this accumulation. Then, PSNPs were proved to activate lipophagy by recruiting LDs into autophagosomes and block the lipophagic flux by impairing lysosomal function, inhibiting LD degradation. Ultimately, PSNPs were shown to activate lipophagy through the AMPK/ULK1 pathway, and knocking down AMPK exacerbated lipid accumulation in hepatocytes. Overall, these results indicated that PSNPs triggered lipophagy via the AMPK/ULK1 pathway and blocked lipophagic flux, leading to lipid accumulation in hepatocytes. Thus, this study identifies a novel mechanism underlying nanoplastic-induced lipid accumulation, providing a foundation for the toxicity study and risk assessments of nanoplastics. Environmental implication Micro- and nanoplastics are emerging pollutants that are widely distributed in the environment, including water, soil and the atmosphere. Currently, they have been detected in various human tissue and organ samples. Therefore, there is an urgent need to address the potential adverse human health effects of micro- and nanoplastics. Nanoplastics have a smaller particle size, which makes it easier for them to pass through the human biological barrier, thus posing a greater potential hazard to humans. Nanoplastics have been found to disrupt liver metabolism and cause lipid metabolism disorders, but the specific mechanism remains uncertain. In this study, we found that PSNPs induced LD accumulation in hepatocytes by activating lipophagy and blocking lipophagic flux to inhibit the lipophagic degradation of LDs. This study provides novel evidence for the toxicological study and health risk assessment of nanoplastics.