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  • Background cardiometabolic diseases inherited metabolic and


    Background: cardiometabolic diseases, inherited metabolic and endocrine disorders
    Biochemistry, physiology, molecular basis and assessment of autophagy Autophagy, a dynamic conservative process to remove long-lived, damaged and aggregated cellular components, came from the Greek, (“auto” - oneself, “phagy” – to eat), which refers to a catabolism process for clearance of aged or injured intracellular components to cope up with cell stress and maintain cellular and organismal homeostasis [26]. The ubiquitin-proteasome system (UPS) and autophagy–lysosome systems represent two major forms of proteolytic mechanisms for protein degradation and recycling. Autophagy, however, is different from the UPS pathway in the manner of bulk degradation of intracellular organelles and protein Dorsomorphin (Compound C) that is absent for UPS [25]. Up-to-date, three main forms of autophagy are known including macroautophagy, chaperone-mediated autophagy (CMA) and microautophagy [20,27,28]. Microautophagy refers to a process of invagination of lysosomal or endosomal membranes, resulting in the engulfment of cytoplasmic cargo. CMA, on the other hand, is governed by heat shock chaperone of 70 kDa, followed by binding of the pentapeptide KFERQ motif to a lysosomal receptor complex, before the delivery of the complex into lysosome for proteolysis [25]. In macroautophagy or autophagy, cytosolic components are surrounded by double-membranes to form autophagosome, prior to the fusion with lysosomes to degrade the sequestered cargo contents [3]. Typical autophagy process includes initiation, elongation and nucleation, autophagosome formation and maturation, as well as vesicle fusion and autophagosome degradation. Autophagy is also classified into selective or non-selective autophagy depending on the nature of cargo contents – namely axophagy (axons), glyophagy (glycogen), lipophagy (lipids), mitophagy (mitochondria), nucleophagy (nucleus), pexophagy (peroxisomes), reticulopathy (endoplasmic reticulum, ER), ribophagy (ribosomes), xenophagy (intracellular pathogens), and zymophagy (zymogen granules) [25].
    Cardiomyopathy in cardiometabolic syndrome Cardiometabolic Dorsomorphin (Compound C) syndrome contributes to cardiac hypertrophy and contractile anomalies [3]. Reduced myocardial perfusion was found in an atherogenic model of cardiometabolic syndrome (including obesity, dyslipidemia and insulin resistance) in swine, with upregulated Atg5 although reduced Beclin1 and LC3BII/I ratio [36]. Using high fat- and/or high cholesterol fed models of cardiometabolic disease, cardiac hypertrophy and contractile anomalies including decreased ejection fraction, fractional shortening, increased ventricular wall thickness, as well as LV end diastolic and systolic diameters (LVEDD, LVESD) were observed [34,37,38]. These changes are accompanied with interstitial fibrosis, build-up of peri-/epicardial fat, glucose utilization for energy (a “fetal pattern” as opposed to fatty acids as the main energy source), alterations in the energy sensors, e.g. AMPK, acetyl CoA carboxylase (ACC) and PGC1α in hearts [37]. Possibly functioning as a compensatory response, a transient hyper-activated state in hemodynamics occurred early in cardiometabolic diseases evidenced by elevated cardiac output and blood pressure [36,39] although such hyper-dynamics may become decompensated, leading to cardiac hypertrophy, compromised systolic and diastolic function [39]. Ample of evidence has depicted the presence of heart failure with preserved left ventricular ejection fraction (HFpEF) in obese patients where severe LV systolic dysfunction is rather uncommon [40]. Besides heart failure, atrial fibrillation is another morbidity usually associated with cardiometabolic disease [41]. A number of mechanisms including hemodynamic, neurohormonal activation, lipotoxicity, oxidative stress, apoptosis and inflammation were postulated for the onset and development of cardiac anomalies in cardiometabolic disease [42,43]. More data suggested that compromised autophagy contribute to cardiac dysfunction in cardiometabolic disease [3,38]. This notion received supports from numerous beneficial cardiac effect of autophagy induction in the face of cardiometabolic disease [3,34,44]. Although cardiometabolic disease-induced autophagy failure still warrants further in-depth research, it is plausible to speculate that nutrient sensors capable of regulating adipogenesis, thermogenesis, lipid metabolism, adipokine synthesis and secretion, may drive autophagy as a downstream effector for these biological responses [3,25].