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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
Free fatty acid synthesis occurs mainly in the liver and adipose tissue. In the liver, the main precursor for fatty acid synthesis is endogenous glucose derived from glycogen, lactate and blood glucose. Pyruvate is the main source of acetyl CoA, and this process is enhanced by raised plasma insulin concentration and lowered glucagon concentration. Acetyl CoA is an important substrate for the synthesis of free fatty acids under the control of acetyl-CoA-carboxylase. The acetyl CoA is converted first to malonyl CoA and then to fatty acid. Citrate formed in the citric acid cycle diffuses out of the mitochondrion and splits into acetyl CoA and oxaloacetate in the cytoplasm (Figure 65.16). The NADPH required for free fatty acid synthesis is supplied by the hexose monophosphate shunt and by the conversion of citrate to pyruvate in the cytoplasm. The hexose monophosphate shunt is highly active in the cytoplasm of the liver and adipose tissue.
Features of Lipid Metabolism in Diabetes Mellitus and Ischemic Heart Disease
Published in E.I. Sokolov, Obesity and Diabetes Mellitus, 2020
The liver and adipose tissue are the main targets of the action of insulin for regulating fat metabolism in an organism. Biochemical investigations showed that an increase in the insulin level in the blood plasma stimulates the synthesis of fatty acids in the liver. This effect is ensured by the following mechanisms: insulin can have a direct stimulating effect on acetyl-CoA-carboxylase — the key enzyme of liposynthesis;diminishing of the supply of FFA (under the influence of insulin) eliminates their inhibiting effect on acetyl-CoA-carboxylase;since insulin stimulates the utilization of glucose along the pentose path, the amount of reduced NADP grows; it is the required hydrogen donor for many stages of fatty acid synthesis;the growth in the flow of glycolysis substrates in the Krebs cycle occurring under the influence of insulin increases the level of citrate that also stimulates acetyl-CoA-carboxylase. The fatty acids synthesized in the liver are then transported (in the composition of VLDLP) into adipose tissue where they accumulate in the form of triglycerides.
Developmental Aspects of the Alveolar Epithelium and the Pulmonary Surfactant System
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
Jacques R. Bourbon, Caroline Fraslon
In addition to the activity of their respective biosynthetic pathways, the synthesis of surfactant phospholipids depends upon the availability of precursors for the synthesis of phosphatidic acid: fatty acids and substrates from the glycolytic pathway. The requirement for endogenous pulmonary fatty acid production in the prenatal period was discussed in chapter 3, Section IV.D. For instance, Patterson and co-workers166 have demonstrated that DSPC biosynthesis in fetal rat lung was dependent upon de novo palmitate supply. Fatty acid biosynthesis in developing fetal lung has been reviewed recently.167 In brief, an enhanced rate of fatty acid synthesis168–170 has been correlated with an increase in activity of fatty acid synthase, the enzyme which catalyzes the final steps in fatty acid synthesis. This increase has been reported during the last gestational days in the rabbit170 and rat171 fetus. Somewhat discrepant data have been reported regarding acetyl-CoA carboxylase activity. In the fetal rat, the latter was reported to peak close to term in two studies168,172 and to decline in another,171 while no change was observed in the fetal rabbit.173 A modest and transient postnatal increase of ATP-citrate lyase was observed in rat lung.172
Biomedical Applications of polymeric micelles in the treatment of diabetes mellitus: Current success and future approaches
Published in Expert Opinion on Drug Delivery, 2022
Jaskiran Kaur, Monica Gulati, Flavia Zacconi, Harish Dureja, Raimar Loebenberg, Md Salahuddin Ansari, Othman AlOmeir, Aftab Alam, Dinesh Kumar Chellappan, Gaurav Gupta, Niraj Kumar Jha, Terezinha de Jesus Andreoli Pinto, Andrew Morris, Yahya E. Choonara, Jon Adams, Kamal Dua, Sachin Kumar Singh
Lifestyle choices were reported to have a strong impact on the development of insulin resistance where chronic inflammation due to obesity is a critical factor. Obesity causes an increase in lipid synthesis, activating the essential enzyme acetyl CoA carboxylase (ACC) by dephosphorylation, leading to the transformation of acetyl CoA to malonyl CoA via carboxylation [38]. An increase in the phosphorylation of ACC reduces non-esterified fatty acid (NEFA) deposition in the peripheral tissue, including the liver. The excessive formation of NEFA inhibits insulin signaling and causes hepatic inflammation potentially leading to the development of T2DM. A higher concentration of NEFA is reported to be associated with an increase in the expression of cyclooxygenase-2 (COX-2) and the monocyte chemoattractant protein-1 (MCP-1) in the hepatocytes [39].
Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system
Published in Expert Review of Neurotherapeutics, 2021
Sarah Demaré, Asha Kothari, Nigel A. Calcutt, Paul Fernyhough
AMPK phosphorylation and activation by metformin was first demonstrated in rat hepatocytes [33]. Metformin induces the phosphorylation and activation of AMPK at T172 in both isoforms of the catalytic α-subunit. Inhibition of acetyl-CoA carboxylase (ACC) and increased fatty acid oxidation were identified as downstream effects. Liver kinase B1 (LKB1), the upstream kinase of AMPK, was implicated as LKB1 knockout mice were resistant to AMPK activation and did not exhibit reduced serum glucose levels following metformin treatment [34]. However, the LKB1-AMPK pathway may not be absolutely required to lower hepatic glucose production [35]. Using mice with defective α1/2 AMPK subunits, metformin decreased intracellular ATP concentration in primary hepatocytes as well as causing an associated drop in hepatic glucose production. Increased levels of AMP, an allosteric activator of AMPK, were also detected.
Synthesis and biological evaluation of 4-phenoxy-phenyl isoxazoles as novel acetyl-CoA carboxylase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Xin Wu, Yongbo Yu, Tonghui Huang
Acetyl-CoA carboxylase (ACC), a crucial enzyme in FASyn, has two subcellular specific isoforms, namely ACC1 and ACC2, which catalyse the carboxylation of acetyl-CoA to malonyl-CoA and display distinct physiological roles9. ACC1 is a cytosolic enzyme that mainly controls the FASyn process, with its product malonyl-CoA extends the fatty acids chain by two carbon increments under the catalysis of fatty acid synthase10. In contrast, the mitochondrial isoform ACC2 is primarily responsible for fatty acid oxidation (FAOxn) through the inhibition of carnitine palmitoyltransferase I (CPT-1) by localised malonyl-CoA production11. Thus, the functional abnormalities on ACC could provide a viable modality for disturbing the energy metabolism and causing cell damage, which facilitates the utilisation of ACC as an attractive therapeutic target12,13. Currently, cancer therapeutics mainly focuses on the ACC1 isoform due to the over-expression of ACC1 mRNA in most human cancers14–18.