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  • APPL was the first adaptor protein identified that interacts

    2023-05-17

    APPL1 was the first adaptor protein identified that interacts directly with adiponectin receptors [18]. A two-hybrid study by Dong and colleagues revealed that the C-terminal extracellular domain of AdipoR1 interacts with adiponectin, whereas the N-terminal cytoplasmic domain of AdipoR1 interacts with APPL1 when stimulated by adiponectin [4]. Importantly, APPL1 interacts with AdipoR1 only when its PTB domain is intact, suggesting that the PTB domain is critical for APPL1 to interact with AdipoR1 [4]. Similarly, APPL1 also interacted with AdipoR2 in a yeast two-hybrid library screen [4], but the interaction domain remains unclear. The essential roles of APPL1 in adiponectin signaling have been demonstrated in many cells, such as skeletal muscle cells, cardiomyocytes, foam cells, umbilical vein endothelial cells, etc. In muscle cells, the glucose-lowering effects of adiponectin are mainly mediated through promoting glucose uptake by the activation of AMPK [53] and the membrane translocation of glucose transporter 4 (GLUT4) in skeletal muscle [56]. APPL1 enhances the cytosolic localization of LKB1 via its BAR domain thereby facilitating phosphorylation of AMPK [57]. Suppression of APPL1 significantly attenuates the adiponectin-stimulated phosphorylation of AMPK, MAPK, and acetyl-CoA carboxylase (ACC) and fatty NSC23766 oxidation [4]. Similarly, adiponectin-stimulated AMPK phosphorylation in the liver is significantly reduced in APPL1 knock-out mice [29]. In hepatocytes treated with adiponectin, APPL1 protein levels are negatively associated with the protein and mRNA levels of gluconeogenesis enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [58]. By modulating the adiponectin-reduced interaction between sirtuin 1 (SirT1) and signal transducer and activator of transcription 3 (STAT3), APPL1 positively regulates adiponectin-stimulated STAT3 activity, thus contributing to the inhibitory effect of adiponectin on hepatic gluconeogenesis [58]. In cardiomyocytes, APPL1 mediates adiponectin induced fatty acid uptake and oxidation [59]. In response to adiponectin, APPL1 binds to AdipoR1 and promotes its interaction with AMPKα2, leading to the phosphorylation and inhibition of acetyl-CoA carboxylase (ACC) and an increase in fatty acid oxidation [59]. Mice fed a high fat diet (HFD) for 16weeks showed significantly increased myocardial contents of distinct ceramide, sphingomyelin, and diacylglycerol (DAG) species and myocyte dysfunction [60]. Over-expression of APPL1 protected mice from HFD-induced increases in circulating nonesterified fatty acid levels, myocardial lipid accumulation, and cardiac dysfunction [60], although the underlying mechanism of these effects is still unknown. Moreover, APPL1 mediates adiponectin-induced Rho/ROCK-dependent cytoskeleton remodeling to increase glucose uptake and metabolism in cardiomyocytes [61]. In human foam cells, both AdipoR1 and AdipoR2 are involved in the action of adiponectin in reducing lipid accumulation and inhibiting foam cell formation [62]. APPL1 is necessary for adiponectin-suppressed foam cell formation since APPL1 knockdown significantly impairs the action of adiponectin on lipid accumulation, AKT phosphorylation, and gene expression of scavenger receptor A type 1 (SR-AI) and NF-κB in macrophage foam cells [62]. Thus, the adiponectin-AdipoR1/2-APPL1 axis may be a potential therapeutic target for preventing macrophage foam cell formation and atherosclerosis. In human umbilical vein endothelial cells, APPL1 serves as a signaling protein that mediates downstream signaling events from adiponectin receptors to eNOS for NO production [23]. RNAi-mediated suppression of APPL1 in endothelial cells blocks adiponectin-stimulated association of heat shock protein 90 (HSP90) with eNOS, which is indispensable for maximal eNOS activity [23]. In cardiac microvascular endothelial cells, APPL1 is involved in adiponectin-regulated cell apoptosis. Adiponectin exerts anti-inflammatory and anti-apoptotic effects via AMPK activation, while interleukin (IL)-18 plays pro-inflammatory and pro-apoptotic roles [63]. Knockdown of APPL1 significantly attenuates adiponectin-induced AMPK phosphorylation and reverses the protective effects of adiponectin on IL-18-induced endothelial cell death, indicating the APPL1-dependent inhibitory effects of adiponectin on vascular injury and inflammation [63].