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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.
Carnitine palmitoyl transferase I 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
Three isoforms of CPT I have been identified [8]. Type IA or H-I, the hepatic isoform, the key regulator of fatty acid metabolism, is defective in CPT I deficiency. It transports long-chain fatty acyl CoAs across the outer mitochondrial membrane. Affected infants have hypoketotic hypoglycemia, but often remain otherwise well. Newborn screening tests reveal elevated free carnitine (elevated C0/C16 + C18). Confirmation of the leukocyte diagnosis is accomplished by assay of the enzyme in fibroblasts. The disorder is detected by newborn screening, with variable sensitivity [9]. Type IB (M-I) is expressed in skeletal muscle. Fatty acid synthesis in the central nervous system is implicated in the control of food intake and energy expenditure. Malonyl CoA is an intermediate in this pathway. Malonyl CoA is an inhibitor of CPT I. CPT Ic knock out (KO) mice have lower body weight and food intake, and this is consistent with the function of malonyl CoA as an energy sensor. Paradoxically, CPT Ic KO mice fed a high-fat diet become obese and have decreased rates of fatty acid oxidation [10]. CPT Ic is found in the brain. Following a high-fat intake, CPT Ic KO mice developed severe insulin resistance, which was considered a result of increased hepatic gluconeogenesis and decreased uptake of glucose by skeletal muscle. Elevated concentrations of nonesterified fatty acids in plasma are thought to be important mediators [11]. Overexpression of CPT Ic in hypothalamus after injection of a CPT Ic adenoviral vector protects mice from obesity [12], confirming a role for CPT Ic in energy homeostasis.
Biochemical Aspects of Fatty Liver
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Treatment with phenobarbital or with other barbiturates (5 mg/100 b.w.) in the rat three times of six to eight intervals (Ugazio et al., 1971) provokes fat accumulation in the liver (Chalvardjian, 1970; Salvador et al., 1970); this is more evident in male than in female rats. It has been claimed that the mechanism consists in stimulation of fatty acid synthesis from acetyl-CoA (Tuma et al., 1974).
Psidium cattleianum fruit extract prevents systemic alterations in an animal model of type 2 diabetes mellitus: comparison with metformin effects
Published in Biomarkers, 2023
Juliane De Souza Cardoso, Fernanda Cardoso Teixeira, Julia Eisenhardt De Mello, Mayara Sandrielly Soares De Aguiar, Pathise Souto Oliveira, Juliane Torchelsen Saraiva, Marcia Vizzotto, Fabiane Borelli Grecco, Claiton Leoneti Lencina, Roselia Maria Spanevello, Rejane Giacomelli Tavares, Francieli Moro Stefanello
Although many studies have demonstrated the beneficial action of natural products in the prevention or treatment of metabolic disorders, the mechanisms involved in these effects have not yet been fully clarified. In this context, phenolic compounds most often seem to decrease lipogenesis and de novo fatty acid synthesis, increase lipolysis, and attenuate inflammation and oxidative stress (Rodríguez-Pérez et al.2019). Gómez-Zorita et al. (2017) found that the phenolic compound hesperidin reduces the expression of genes involved in the three phases of adipocyte synthesis (c/ebpβ, srebp1c, and perilipin) and reduces TG levels in the cell. In contrast, apigenin does not affect the expression of these genes or TG levels. Apigenin, hesperidin, and kaempferol stimulate the mRNA expression of the lipase enzyme, which is responsible for fat degradation (Gómez-Zorita et al.2017). Inactivated lipase is unable to hydrolyse fats, which then pass freely through faeces without being absorbed. Several natural products, such as extracts and infusions of grape seeds (Vitis vinifera); white, green, and black tea (Camellia sinensis); and pomegranate (Punica granatum) leaves, have been shown to inhibit lipase and fatty acid synthase, and are considered anti-obesity phytochemicals (Rodríguez-Pérez et al.2019).
New insights into the metabolism of Th17 cells
Published in Immunological Medicine, 2023
Fatty acid oxidation is a mitochondrial aerobic process responsible for producing acetyl CoA from fatty acids. In contrast, fatty acid synthesis is the creation of fatty acids from acetyl CoA and Nicotinamide adenine dinucleotide phosphate (NADPH) [13]. Adenosine monophosphate-activated protein kinase (AMPK), a serine/threonine kinase, is a vital metabolic regulator that inhibits mTORC activity. AMPK-dependent phosphorylation of acetyl-CoA carboxylase 1 (ACC1) is the rate-limiting enzyme for fatty acid synthesis. ACC1 modulates the DNA binding of RORγt to target genes and enhances Th17 cell differentiation [79–81]. Cholesterol is synthesized from acetyl CoA by the hydroxymethylglutaryl-coenzyme A (HMG-CoA). Statin, an inhibitor of HMG-CoA reductase, reduces Th17 cell differentiation [82].
Proton Pump Inhibitor Use and Obesity-Associated Cancer in the Women’s Health Initiative
Published in Nutrition and Cancer, 2022
Tarah J. Ballinger, Zora Djuric, Sagar Sardesai, Kathleen M. Hovey, Chris A. Andrews, Theodore M. Brasky, Jian Ting Zhang, Thomas E Rohan, Nazmus Saquib, Aladdin H. Shadyab, Michael Simon, Jean Wactawski-Wende, Robert Wallace, Ikuko Kato
Human fatty acid synthase (FASN) plays a critical role in lipogenesis as the sole cytosolic enzyme responsible for de novo synthesis of palmitate via the condensation of acetyl-CoA and malonyl-CoA (7). Expression of FASN is regulated by energy balance. Exercise and caloric restriction downregulate FASN, while FASN is upregulated in obesity and functions to store excess glucose as lipids in adipose depots (8–10). The typical Western diet contains sufficient free fatty acids such that FASN is not required for normal cell function; therefore, its expression is very low in normal cells with the exception of lactating breast, cycling endometrium, and adipose tissue (11). In contrast, cancer cells require de novo fatty acid synthesis for survival (12). Conversely, inhibition of FASN induces apoptosis selectively in cancer cells In Vitro and In Vivo, with minimal effect on nonmalignant cells (13, 14). Thus, it is an ideal potential target for prevention of cancer development, and it is hypothesized that inhibitors of FASN may have chemopreventive effects (15).