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Inborn Errors of Metabolism
Published in Praveen S. Goday, Cassandra L. S. Walia, Pediatric Nutrition for Dietitians, 2022
Surekha Pendyal, Areeg Hassan El-Gharbawy
FAO provides as much as 80% of energy for heart and liver function. In the liver, the oxidation of fatty acids fuels the synthesis of ketone bodies which are utilized as an alternative energy source by extrahepatic organs, particularly the brain. Glucose is the preferred energy source in cells and glucose derived from glycogen is used during short-term fasting. During periods of prolonged fasting, febrile illness, or increased muscular activity, fatty acids are mobilized to meet the increased energy demands. The physiologically available fatty acids are mostly the C16 and C18 (long-chain) fatty acids and their oxidation requires entry into the mitochondrial matrix using enzymes of the carnitine shuttle (Figure 23.3, steps 1–3). Once inside the mitochondria, β-oxidation of the fatty acids occurs in a repeating cycle using the four enzyme complexes (Figure 23.3, steps 4–7), each “spiral” of the cycle releasing one molecule of acetyl-CoA and leaving a fatty acyl CoA two carbons shorter for recycling through further β-oxidation. Acetyl-CoA can then enter the citric acid (CA) cycle and/or serve as the precursor for ketone production. The reducing equivalents reduced nicotinamide adenine dinucleotide (NADH) and dihydroflavine adenine dinucleotide (FADH2) produced from β-oxidation and the CA cycle enter the electron transport chain for adenosine triphosphate (ATP) production.
Lipids and Lipid Metabolism in Postnatal Gut Development and Risk of Intestinal Injury
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Utilization of fatty acids at the cellular level begins with internalization of the fatty acid into the cell via fatty acid transporters. Once within the cell, the fatty acid is converted to fatty acyl-CoA via fatty acyl-CoA synthase (Figure 49.2). At the outer membrane of the mitochondria, carnitine palmitoyltransferase 1 converts the fatty acid-CoA to fatty acyl carnitine. Fatty acyl carnitine then crosses the inner mitochondrial membrane through a carnitine exchange via carnitine-acyl carnitine translocase. Once inside the mitochondrial matrix, the fatty acyl carnitine is converted back to fatty acyl-CoA via carnitine palmitoyltransferase 2, allowing for entry into the β-oxidation pathway generating acetyl-CoA. Acetyl-CoA is utilized by the tricarboxylic acid cycle (TCA) cycle to form NADH and FADH2.
Carnitine transporter deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The metabolism of fat begins with lipolysis; those patients with defective fatty acid oxidation have high ratios of free fatty acids to 3-hydroxybutyrate in blood after fasting. Once transported into cells, carnitine is esterified with acyl CoA esters, including those of fatty acids resulting from lipolysis. The esterifications are catalyzed by carnitine acyl transferases, such as carnitine palmitoyl transferase (CPT) I. Carnitine translocase then catalyzes the transfer of the fatty acylcarnitines across the membrane into the mitochondrion, where hydrolysis to fatty acyl CoA and free or recycled carnitine is catalyzed by CPT II. Fatty acyl CoA compounds then undergo β-oxidation in which there is successive shortening by two carbon atoms releasing acetyl CoA. In muscle, this is largely oxidized via the citric acid cycle, while in the liver ketogenesis proceeds via the successive action of 3-hydroxymethylglutaryl (HMG) CoA synthase and lyase-yielding acetoacetate, which is converted to 3-hydroxybutyrate.
Not just a gut feeling: a deep exploration of functional bacterial metabolites that can modulate host health
Published in Gut Microbes, 2022
First, Liu et al. discovered a microbially manufactured metabolite, delta-valerobetaine (VB), was able to impair mitochondrial β-oxidation, leading to accumulation of circulating long chain fatty acyl CoA.15 This metabolite was shown to impair fatty acid oxidation in mice, while subsequently eliciting upregulation of downstream genes of peroxisomal proliferator-activated receptor alpha (PPARα), which is somewhat puzzling given the role of PPARα in promoting lipolysis.15,51 However, this trend was reversed with the feeding of a “Western Diet”, consisting of high fat and sugar chow, which, when administered concomitantly with VB, led to an increase in perigonadal visceral adipose tissue, posterior subcutaneous adipose tissue, and interscapular brown adipose tissue, as well as exacerbated hepatic steatosis.15 Similar trends were observed in human subjects in a clinical setting, where increased plasma VB was correlated with increased visceral adipose tissue, increased BMI, and increased incidence of hepatic steatosis.15 This finding suggests that not only are gut microbes able to alter host weight status through mechanisms unrelated to CVD, but these mechanisms are also significantly modulated by host diet.
Logistic role of carnitine shuttle system on radiation-induced L-carnitine and acylcarnitines alteration
Published in International Journal of Radiation Biology, 2022
The pool of L-carnitine and even-chain acylcarnitines redistribution in serum and urine after irradiation can directly point to altered FAO homeostasis. FAO mainly occurs in mitochondria which is the primary target organelles of radiation (Kam and Banati 2013). As dietary derived or adipose tissue releases the main type of fatty acids, long-chain fatty acids as energy substrates need more than 20 different enzymes and transport proteins to be imported into mitochondria. In particular, the mitochondrial membrane is impermeable to fatty acyl-CoA, and long-chain fatty acids must be conjugated to L-carnitine to enter mitochondria. Thus, the specialized carnitine shuttle system that transports the fatty acids into mitochondria has a key role in controlling the flux of FAO (Mutomba et al. 2000; Han et al. 2019).
Relationship between the effect of polyunsaturated fatty acids (PUFAs) on brain plasticity and the improvement on cognition and behavior in individuals with autism spectrum disorder
Published in Nutritional Neuroscience, 2022
Isabel Barón-Mendoza, Aliesha González-Arenas
The FATPs are a family of six membrane proteins expressed differentially in adipose tissue, brain, heart, liver and muscle. In the brain, FATP1 and FATP4 are highly expressed. It has been reported that in humans, FATPs show bifunctionality; they display a binding motif for fatty acids to import them into the intracellular space, and also, an ATP- binding motif involved with their intrinsic activity of long-chain acyl-coenzyme A synthetase, which catalyzes the free-PUFAs transformation to their respective fatty acyl-CoA thioesters during its transport across the membrane [27,28]. The conversion of free PUFAs to thioesters is called the activation phase, which is a precondition for further elongation and desaturation processes, as well as for PUFAs oxidation in the mitochondrial or peroxisomal compartment, and the biosynthesis of glycerolipids, triacylglycerols and eicosanoid-derivatives [29].