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  • Autophagy plays an essential role in the maintenance

    2019-07-24

    Autophagy plays an essential role in the maintenance of cellular homeostasis. Dysregulation of autophagy may participate in the pathogenesis of cardiovascular and metabolic diseases [29]. Regulation of autophagy is accomplished through essential nutrient and P 22077 sensors including mechanistic target of rapamycin (mTOR), AMP-dependent protein kinase (AMPK), and insulin-insulin-like growth factor I (IGF-1) cascade. AMPK and mTOR function as the main positive and negative regulators, respectively, of autophagy through phosphorylation of their downstream target ULK1. In cardiometabolic stress with nutrient excess, hyperactivation of mTOR is perhaps the main “metabolic check-point” for autophagy failure as sustained activation of mTOR complex results in autophagy inhibition and onset of various myopathies [3,30]. In addition to the above-mentioned signaling molecules, a number of receptors, pro-inflammatory cytokines as well as innate and adaptive immune regulators also participate in the regulation of autophagy [31]. Functional autophagy plays an important role in the maintenance of cellular and organismal homeostasis through removal of protein aggregates, lipid droplet and injured organelles, recycling of metabolic components including amino acids, lipids and other metabolic precursors, as well as facilitation of immune response in stress condition such as inflammation through degrading intracellular bacteria and viruses. Lack of autophagy predisposes organisms to metabolic anomalies, inflammation and immune deficiency [25]. Initiation of autophagy in the face of starvation and inflammation inhibits proinflammatory cytokine response, inflammasome maturation and cytokine release [29], validating its unique role in the preservation of cardiometabolic function. Altered autophagy (or autophagy failure) may serve as both causes and consequences for metabolic disorders. Table 1 lists autophagy change in a number of individual components of metabolic syndrome. On the other hand, deficiency in autophagy predisposes to fat diet-induced insulin resistance, obesity and transition into type 2 diabetes mellitus [25]. Table 2 provides the “proof-of-concept” cardiovascular and metabolic pathologies of autophagy overexpression or deletion. As an effective measure to self-replenish energy store upon exhaustion of exogenous resources, autophagy has drawn some great interest in cardiometabolic diseases with nutritional excess such as obesity, insulin resistance and diabetes mellitus [25]. For example, impairment of adipocyte autophagy is present in subcutaneous fat cells from obese patients, resulting in lipid overload and hypertrophy in adipocytes. Such defect may be alleviated following gastric bypass surgery and weight loss, denoting the important role of autophagy in the regulation of adipocyte size and lipid content. In addition, defective autophagy of obese adipocytes may be related to the loss of DAPK2 (death-associated protein kinase 2), a modulator for autophagic flux [32]. Thus, disruption of adipocyte autophagy may contribute to low-grade chronic inflammation, adipose tissue deterioration and lipid accumulation in obesity [32]. It is noteworthy that assessment of autophagy may be challenging and misleading in cases, making examination of autophagy to be somewhat difficult. A rise in autophagosomes suggests either enhanced formation of LC3B or reduced lysosomal clearance (autophagy flux). For better assessment of autophagy flux, protein markers of early autophagosome formation (LC3B) and late lysosomal degradation (p62) need to be evaluated to pinpoint autophagy activity [33]. Typically, increased LC3B along with loss of p62 would denote activated autophagic flux. In contrary, accumulation of LC3B and p62 as seen in our high fat diet model suggests interrupted autophagic flux [34]. The gap in LC3B detected in the presence or absence of lysosomal inhibition refers to lysosomal degradation [26]. Advance in fluorescent microscopy also makes it possible to visualize autophagosomes [green fluorescent protein (GFP)] and autophagolysosomes [red fluorescent protein (RFP)] based on pH value [35].