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Metabolic Substrates Fatty Acid Utilization Biology Essay

In the cytosol, free fatty acids undergo esterification to become CoA which generates a fatty acyl CoA moiety through an ATP dependent process catalyzed by a family of fatty acyl CoA synthase (FACS) enzymes (Figure 3). The fatty acyl CoAs are then taken into cardiac mitochondria in the form of complex proteins formed by fatty acylcarnitine moieties using the carnitine palmitoyl-transferase-1 (CPT-1) located in the outer membrane of mitochondria and then are converted back into fatty acyl CoAs using the CPT-2 located in the inner mitochodrial membrane.13

In the mitochondria, fatty acid β-oxidation sequentially shortens fatty acyl CoA molecules and liberates acetyl CoA, which is further metabolized in the Kreb’s cycle, while also generating reducing equivalents (NADH and FADH2) which act as electron donors for the electron transport chain and the process of oxidative phosphorylation (Figure 3).14 Important factors regulating the rate of fatty acid β-oxidation are the levels of circulating free fatty acids in the plasma and the activity of CTP-1 in the outer mitochondrial membrane.13

Glucose utilization

Glucose enters the cell via glucose transporters (GLUT), primarily GLUT-4 and to a lesser extent GLUT-1.17 Once in the cytosol, glucose is converted to pyruvate via the glycolysis pathway (Figure 3).14 Under physiological conditions, the pyruvate from glycolysis is then shuttled into the mitochondrial matrix where it will undergo oxidative phosphorylation.14 During the process of oxidative phosphorylation, pyruvate decarboxylation to acetyl CoA is the key irrversible step which is catalyzed by pyruvate dehydrogenase (PDH) (Figure 3).14 However, under ischemic conditions, pyruvate can be converted to lactate in the cytosol in a process of non-oxidative glycolysis thus resulting in decreased levels of pyruvate entering the mitochondria to undergo the oxidative phosphorylation process.14 In cardiac mitochondria, PDH is activated by PDH phosphatase and deactivated by PDH kinase.14 Moreover, inhibition of PDH causes an uncoupling between glycolysis and glucose oxidation resulting in an accumulation of pyruvate as well as decreased acetyl CoA levels.14 In contrast, activation of PDH can increase the coupling of these processes.14

Interregulation of Fatty Acid and Glucose Oxidation

In normal adult hearts, the primary metabolic substrates are fatty acids, accounting for 60-80% of the total energy produced in the heart.13,14 This carefully maintained balance of substrate utilization is regulated by the reciprocal relationship between fatty acid and glucose oxidation. In cardiac mitochondria, the rate of fatty acid oxidation is the primary physiological regulator of flux through PDH and the rate of glucose oxidation (Figure 2). High rates of fatty acid oxidation have been shown to inhibit PDH activity via an increase in mitochondrial acetyl CoA which activates PDH kinase leading to phosphorylation and inhibition of PDH thus resulting in the inhibition of the glucose oxidation process.14 It has been shown that the inhibition of glucose oxidation can lead to an uncoupling between the rates of glycolysis in the cytosol and glucose oxidation in the mitochondria. This subsequently results in lactate accumulation leading to intracellular acidosis (Figure 2).13,14

On the contrary, inhibition of fatty acid oxidation leads to a reduction in acetyl CoA in the mitochondrial matrix thereby attenuating the inhibition of PDH (Figure 2).13,14 Furthermore, inhibition of fatty acid oxidation has been shown to increase glucose and lactate uptake and oxidation by decreasing citrate levels thus attenuating the inhibition of phosphofructokinase (PFK), a key regulatory enzyme in the glycolytic process (Figure 2). Partial inhibitors of myocardial fatty acid oxidation have also been shown to increase pyruvate oxidation with less lactate and proton accumulation.13,14 Taken together, these events result in an enhancement of coupling between glycolysis and glucose oxidation.13,14

Regulation of the mitochondrial metabolic phenotype

The myocardial metabolic phenotype is defined as the substrate preference of the heart in a given metabolic environment, hemodynamic condition, and inotropic state.14 This metabolic phenotype in the heart has been shown to depend on the content of proteins (enzymes and transporters) that facilitate flux into metabolic pathways as well as the structure and integrity of organelles, such as mitochondria, that are responsible for metabolism.14 In the human heart, the metabolic phenotype changes from the fetal and immediate newborn stage, where glucose acts as the primary metabolic substrate via glycolysis, to the newborn and adult stage, which uses fatty acids as the primary substrate via fatty acid oxidation (Figure 1).14,16,18 In the fetal heart, less than 20% of ATP requirements are provided by fatty acid oxidation.16 However, this increases by up to 10-fold, accompanied by a decrease in glucose oxidation, after birth.16 Along with the metabolic shift that occurs during maturation (fetal to adult) of the heart, key enzymes involved in fatty acid oxidation are also altered and are characterized by a change in the CPT-1 ratio. In the fetal heart, CPT-1α is greater relative to CPT-1β, whereas in the adult heart CPT-1β is greater relative to CPT-1α.13,19


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