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APPL1 (Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1), formerly known as APPL or DIP13α, is an adaptor protein that binds directly to the adiponectin receptor. APPL1 is widely expressed in adiponectin and insulin target tissues, such as skeletal muscle, liver endothelium, white adipose tissue, islet cells, ovary, etc. The expression of APPL1 is altered by physiological or pathological factors such as obesity and hyperglycemia. The phosphotyrosine binding (PTB) domain of APPL1 binds to the cytoplasmic domain of adiponectin receptors 1/2 (AdipoR1/2), regulates the secretion of adiponectin and its The effects of metabolism. The PH (pleckstrin homology) domain of APPL1 binds to the small GTPase Rab5 and plays a role in endocytosome-mediated signal transduction. Rashid et al. found that the PH domain of APPL1 bound to the BAR (Bin /Amphiphiphysin /Rvs) domain and Reptin. This unique and mutually exclusive structure can mediate the nuclear transfer of Reptin and participate in the development and progression of cancer.
APPL1 and Insulin Sensitivity
Studies have shown that pancreatic islet cell line INS-1 cells overexpress APPL1 by adenovirus transfection, and found that high glucose, cytokine interleukin-1β (IL-1β) and tumor necrosis factor α (tumor necrosis factor- α, TNF-α) can down-regulate APPL1 protein expression in islet cells, while APPL1 overexpression can prevent high glucose and inflammatory factors from promoting apoptosis and inhibiting glucose insulin secretion. This experiment proved that APPL1 had a protective effect on islet β cells: APPL1 reduced apoptosis and improved glucose-stimulated insulin secretion. The current study has confirmed that the expression levels of serum and renal glucose, cytokines IL-1β and TNF-α in patients with type 2 diabetes are significantly increased, and as an important injury factor for DKD, APPL1 is associated with diabetic kidney disease (DKD).
Adiponectin exerts hypoglycemic, insulin sensitivity, and anti-inflammatory effects by binding to adiponectin receptors on the cell membrane. APPL1 plays an important role in adiponectin signaling and provides a molecular mechanism for adiponectin to enhance insulin sensitivity. APPL1 is involved in the pathway of adiponectin-enhanced insulin sensitivity: APPL1 directly activates adiponectin-mediated AMPK (adenosine 5'-monophosphate-activated protein kinase) pathway by interacting with the phosphatidylinositol 3-kinase(PI3K) subunits p85 and p110. APPL1 also activates the AMPK pathway by anchoring liver kinase B1. Gao et al. demonstrated that APPL1 can also enhance insulin signaling by directly binding to the cytoplasmic regions of the insulin receptors AdipoR1 and AdipoR2.
Ryu et al. showed that compared with wild mice, the insulin and glucose levels in the plasma of APPL1 knockout mice were significantly increased, and the expression of uncoupling protein 1 in brown adipose tissue in brown fat was enhanced. Insulin pathway conduction is inhibited after increasing fat consumption. It was confirmed that APPL1 enhances insulin sensitivity by promoting binding of insulin receptor substrates 1 and 2 to the insulin receptor. In summary, APPL1 may be involved in the occurrence and development of DKD.
Figure 1. Adiponectin Stimulates the Interaction between APPL1 and IRS1. Ryu, et al. 2014).
APPL1 and IR-related Inflammatory Response
APPL1 participates in many inflammation, especially involved in insulin resistance (IR). Some factors play an important role in IR, such as TNF-α, resistin, and TRAF-6 (tumor necrosis factor receptor-associated factor-6). Cheng et al. have confirmed that adiponectin can counteract the production of pro-inflammatory adipokines or cytokines through the insulin signaling pathway. Adiponectin can also inhibit the release of TNF-α secreted by stromal vascular cells and adipocytes. As a result, Over-expressed APPL1 plays a key role in the insulin signaling pathway through stimulating insulin-mediated phosphorylation of AKT. So APPL1 inhibits the release of TNF-α via the adiponectin signaling pathway. The above-mentioned Cheng et al. used adenovirus transfection to overexpress APPL1 in islet cell line INS-1 cells. It was found that high glucose and TNF-α down-regulated APPL1 protein expression in islet cells, and overexpression of APPL1 prevented high glucose and TNF-α. The effect on apoptosis suggests that APPL1 can improve insulin resistance by reducing the inflammatory effects of TNF-α.
Benomar et al. showed that chronic injection of resistin in the hypothalamus of mature male mice enhances the down-regulation of APPL1 and AdipoR1 by negatively regulating adiponectin signaling, while it does not downregulate APPL2 and AdipoR2, regardless of whether Injecting resistin into the hypothalamus or hepatocytes of mice can attenuate or even completely abolish the association between APPL1 and AKT through the AKT /APPL1 /TRB3 pathway. However, the association between AKT and TRB3 is weakened in the hypothalamus and enhanced in the liver. In other words, an increase in resistin can produce IR through the AKT /APPL1 /TRB3 pathway.
Studies have shown that in mouse hepatocytes, lysine 160 is anchored in the BAR domain of APPL1, which is the main site of ubiquitination of APPL1. TRAF-6 is a ubiquitinated ubiquitin ligase of APPL1, inhibiting the expression of TRAF-6 significantly impairs insulin-mediated ubiquitination of APPL1, leading to damage of insulin-stimulated AKT activation and inhibition of downstream substrate GSK-3β and hepatic gluconeogenesis, suggesting that a decrease in TRAF-6 expression leads to IR.