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Metabolism
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The combustion of fatty acids, the major energy component of fats, commences with their activation to CoA derivatives such as palmitoyl CoA. Palmitoyl CoA must be first converted to palmitoylcarnitine by carnitine-palmitoyltransferase in the outer mitochondrial membrane before it can enter the mitochondrion. At the inner mitochondrial membrane, palmitoyl carnitine is reconverted to palmitoyl CoA and then oxidized by β-oxidation, which releases two carbon compounds as acetyl CoA until the entire fatty acid molecule is broken down. β-Oxidation of free fatty acids provides a major source of acetyl CoA, an important substrate for the citric acid cycle. Free fatty acids in blood, derived from the diet or by the action of lipoprotein lipase on lipoproteins at the endothelial cell layer of tissue, are oxidized in the mitochondria. Growth hormone and glucocorticoid increase the mobilization of fat stores by increasing the amount of triglyceride lipase. Initially, free fatty acid is converted to acyl CoA utilizing one ATP. Acyl CoA is oxidized to acetyl CoA, and the residual carbon atoms re-enter the cycle to produce more acetyl CoA (Figure 65.6). This partial oxidation of free fatty acids produces hydrogen ions that are removed as NADH and reduced flavoproteins.
Very long-chain acyl-CoA dehydrogenase 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
Very long-chain acyl-CoA dehydrogenase (VLCAD) is bound to the inner mitochondrial membrane. It was first delineated in 1992 [1] as catalyzing the dehydrogenation of acylCoA esters of 14 to 20 carbon length in the first step of mitochondrial fatty acid oxidation (Figure 40.1). Within one year, there were three reports [2–4] of patients with deficiency of VLCAD, including some who had been previously reported as having long-chain acyl-CoA dehydrogenase (LCAD) deficiency [5]. It is now recognized that all of the patients initially described with LCAD deficiency [6] appear, in retrospect, to have had defects in VLCAD [5]; and the LCAD enzyme catalyzes the specific oxidation of branched long-chain acylCoAs. The usual assay with palmitoyl CoA as substrate in the presence of electron transfer flavoprotein (ETF) would register deficiency of activity if either LCAD or VLCAD was deficient. The distinction can be made by immunochemical or genetic analyses.
Biochemical Aspects of Fatty Liver
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
An example of block of mRNA synthesis related to lack of substrates is that occurring after treatment with d-galactosamine. This substance has been extensively used by Keppler et al. (1968; Keppler, 1976; Keppler and Decker, 1969), at the dose of 200 mg/kg b.w.t. in the rat. Morphologically, dilatation of the cisternae of the SER, degranulation of the RER, decline in glycogen granules, and appearance of a number of autophagic vacuoles take place within a few minutes. At 2 h after injection, severe damage affects nucleoli, which undergo a fibrillar disintegration (Scharnbeck et al., 1972). At 3 h palmitoyl-CoA oxidation in mitochondria strongly decreases (Mangheney-Andreani et al., 1982). 5′-Nucleotidase, a marker of plasma membranes, decreases strongly at 2–3 h (El-Mofty et al., 1975).
Fructose and hepatic insulin resistance
Published in Critical Reviews in Clinical Laboratory Sciences, 2020
Samir Softic, Kimber L. Stanhope, Jeremie Boucher, Senad Divanovic, Miguel A. Lanaspa, Richard J. Johnson, C. Ronald Kahn
Fructose is a highly lipogenic macronutrient, which stimulates hepatic DNL to a greater extent than it’s commonly compared counterpart glucose or even a HFD [6,24,25]. In our studies in chow and HFD-fed mice, 30% (W/V) fructose supplementation for 10 weeks induced a greater increase in enzymes regulating fatty acid synthesis, such as adenosine triphosphate (ATP) citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), compared to mice receiving an equal amount of glucose [10]. Increased protein and mRNA levels of these DNL enzymes correlate with increased endogenous fatty acyl-CoA production, especially palmitoyl-CoA, in livers of fructose-, as compared to glucose-supplemented mice. A HFD itself did not robustly increase DNL enzymes and, interestingly, the effects of fructose were more robust on chow, than when paired with a HFD [10]. Human studies have also shown that carbohydrates support DNL more robustly than a HFD [26] and that fructose stimulates DNL more strongly than glucose [8,27,28] or starch [19].
Aberrant lipid metabolism as a therapeutic target in liver cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Evans D. Pope, Erinmarie O. Kimbrough, Lalitha Padmanabha Vemireddy, Phani Keerthi Surapaneni, John A. Copland, Kabir Mody
De novo fatty acid (FA) synthesis occurs in high energy or fed states. During FA synthesis, glucose is taken up in the liver where it is then converted to FAs for storage in the form of triacylglycerols (TAGs) [8]. The initial step in FA synthesis is glycolysis. Glycolysis results in the production of pyruvate from glucose [8]. This reaction takes place in the cytosol of the hepatocyte. After pyruvate has been produced, pyruvate enters into the mitochondria and is converted to citrate via the citric acid (TCA) cycle [9]. Once citrate has been formed, citrate is expelled out of the mitochondria via the citrate shuttle. Citrate is converted into oxaloacetate and acetyl CoA via ATP-citrate lyase (ACL) [9]. The oxaloacetate is further broken down into pyruvate and NADPH. The acetyl CoA and NADPH are then used for FA synthesis [9]. Acetyl CoA is converted to Malonyl CoA via ACC [10]. Malonyl CoA and Acetyl CoA are combined using FASN to help form saturated fatty acids (SFA) (palmitoyl-CoA and stearoyl-CoA) [10]. Critically, these are then converted to monounsaturated fatty acids (MUFA) palmitoleoyl-CoA and oleoyl-CoA by SCD [11]. MUFAs are critical as building blocks for membrane synthesis, prostaglandin synthesis, and as the source for TAGs. They are important to cancer cell survival via their role in the induction of autophagy, enhancement of cell membrane turnover, effecting intracellular signaling and gene transcription, and increasing energy production.
Validation of urinary sphingolipid metabolites as biomarker of effect for fumonisins exposure in Kenyan children
Published in Biomarkers, 2019
Ruth Nabwire Wangia, David Peter Githanga, Kathy Siyu Xue, Lili Tang, Omu Aggrey Anzala, Jia-Sheng Wang
The mechanism of FB1 toxicity is attributed to its structural similarity to sphingoid bases, which consists of twenty-carbon backbone as shown in Figure 1 (Wang et al.1991). Due to its structural similarity to sphingoid bases, fumonisin B1 acts as a competitive inhibitor of ceramide synthase (Marasas et al. 2004, Riley et al.2012). The de novo pathway of sphingolipid synthesis is highly dependent on the action of ceramide synthase. The process begins with the condensation of serine and palmitoyl-CoA. This condensation is catalyzed by serine palmitoyl transferase to generate 3-ketodihydrosphingosine which is subsequently reduced to sphinganine (Sa). Sa is then N-acylated by ceramide synthase to produce dihydroceramide (dhc) that through the action of dhc-desaturase is reduced to ceramide. In the presence of fumonisin exposure, FB1 inhibits the N-acylation process by blocking ceramide synthase (Turner et al.1999, Voss et al.2002, 2006, Zitomer et al.2009). Ultimately, this inhibition results in accumulation of intracellular Sa that can eventually lead to oxidatively generated DNA damage, sphingomyelin depletion and altered function of sphingolipids as second messengers