Apigenin Reduces\nLipid Droplet Accumulation in Hepatocytes\nby Enhancing Chaperone-Mediated Autophagy via AMPK

Apigenin (4′,5,7-trihydroxyflavone) is a significant\nnatural\nflavonoid compound that is abundantly found in various fruits and\nvegetables. It has been demonstrated to alleviate nonalcoholic fatty\nliver disease and exhibit lipid-lowering effects. However, its impact\non lipid droplet (LD) degradation in hepatocytes remains unclear.\nLDs, coated by perilipins (PLINs), are selectively exposed and degraded\nthrough chaperone-mediated autophagy (CMA), specifically targeting\nPLIN2 and PLIN3 to enhance lipolysis and lipophagy. Lysosome-associated\nmembrane protein type 2A (LAMP-2A) is the rate-limiting component\nof CMA. We found that apigenin-alleviated high-fat diet induced LD\naccumulation in hepatocytes by promoting CMA. The data indicated that\napigenin could improve the expression of LAMP-2A, while downregulating\nthe expression of PLIN2 and PLIN3, reduce the volume and size of LDs.\nAMP-activated protein kinase (AMPK) plays a crucial role in activating\nnuclear factor erythroid 2-related factor 2 (Nrf2), in turn, regulating\nthe transcription of LAMP-2A. In our study, we found that the activation\nof AMPK induced by apigenin promotes PLIN2 phosphorylation and Nrf2\nnuclear translocation, thus subsequently enhancing the activity of\nCMA. This accelerated the degradation of PLINs, ultimately facilitating\nLD degradation. Overall, our study offered valuable insights into\nthe mechanism of apigenin in the degradation of LDs.