Conclusion
David N. Brindley, John R. Sabine in Phosphatidate Phosphohydrolase, 2017
The discussion in this book has naturally centered around phosphatidate phosphohydrolase and its possible roles in controlling glycerolipid synthesis. This is not intended to imply that other sites of regulation for glycerolipid synthesis are unimportant. For example, the availabilities of substrates such as glycerol phosphate, dihydroxyacetone phosphate, fatty acids, and CDP choline can vary dramatically in different physiological conditions and thus will have a major influence on the rates of glycerolipid synthesis in different tissues. Furthermore, the activities of glycerol phosphate acyltransferase, diacylglycerol acyltransferase, and CTP:phosphocholine cytidylytransferase may change relative to that of phosphatidate phosphohydrolase. This is likely to be tightly coordinated so as to effect an overall change in the balance between the various routes of fatty acid metabolism and other metabolic processes.
Nutrient Interactions and Glucose Homeostasis
Emmanuel C. Opara, Sam Dagogo-Jack in Nutrition and Diabetes, 2019
According to the original Randle hypothesis, an increase in fatty acid availability results in increased fatty acid oxidation with concomitant inhibition of glucose oxidation. Various mechanisms are involved in the inhibition of glucose oxidation during increased fatty acid supply and oxidation, as illustrated in Figure 12.1. The accumulation of acetyl-CoA would result in the inhibition of pyruvate dehydrogenase (PDH), while the abundance of citrate would inhibit phosphofructokinase (PFK), and excess levels of glucose-6-phosphate (G-6-P) would inhibit the activity of hexokinase (HK) [12,13]. There has also been an accumulation of evidence to show that increases in the glycolytic flux during glucose metabolism may decrease fatty acid oxidation. It has been proposed that the potential sites of fatty acid metabolism affected include the transport of fatty acid into the sarcoplasma, lipolysis of intramuscular triacylglycerol by hormone-sensitive lipase, and transport of fatty acids across the mitochondrial membrane [12]. One scenario among the possible mechanisms of regulation of fatty acid metabolism is an increase in malonyl-CoA concentration, which is formed from acetyl-CoA in a reaction catalyzed by acetyl-CoA carboxylase (ACC). Increased levels of malonyl-CoA will inhibit carnitine palmitoyl transferase 1 (CPT1) [14]. Indeed, using muscle biopsies obtained from obese subjects for lipid analysis and reverse transcription-competitive polymerase chain reaction, it has been shown that down-regulation of ACC2 mRNA, induced by lowering plasma insulin levels, caused improvement in insulin sensitivity [15].
Dietary supplements and food fortification
Geoffrey P. Webb in Nutrition, 2019
Vitamin D could qualify as conditionally essential because a dietary supply is only necessary if there is inadequate sunlight to allow cutaneous synthesis of the vitamin. Carnitine is a cellular component that is synthesised from the amino acid lysine. It is essential for fatty acid metabolism but healthy people normally synthesise enough carnitine to satisfy their physiological needs, even those who are strict vegetarians and get almost none from their diet. There are several rare inherited disorders of fatty acid metabolism in which carnitine becomes an essential nutrient. It is also widely regarded as essential for infants especially if they are premature. The amino acid glutamine may become essential in people with serious illness or injury because utilisation exceeds synthesis in such patients and plasma glutamine concentrations drop. Some clinical trials have shown that supplemental glutamine may have beneficial effects in these circumstances. The amino acids cysteine and tyrosine are conditionally essential for premature infants because the enzymes for their synthesis do not develop until the end of gestation.
Proteomic profiling of fatty acid binding proteins in muscular dystrophy
Published in Expert Review of Proteomics, 2020
Paul Dowling, Stephen Gargan, Margit Zweyer, Dieter Swandulla, Kay Ohlendieck
Fatty acid metabolism occurs in most mammalian tissues, but adipose tissue, skeletal muscles and the liver present the three key systems that regulate through intrinsic interactions the efficient uptake, transport, release and utilization of fatty acids and storage of high-energy fat molecules. Under physiological conditions, fats are obtained from various sources, i.e. fat molecules in the diet, triacylglycerol stored in specific cells and mobilization of fats stored as fat droplets in adipose tissue, as well as conversion of excess dietary carbohydrate to fats in the liver for export to other tissues. The overall regulation of oxidative metabolism is a highly coordinated process that is especially challenged during periods of extreme changes in the body in relation to food supply and contractile activity levels. Repeating cycles of diverse dietary intake with complex variations in the composition and amount of different types of food molecules versus periods of no access to energy-rich molecules during extended phases of sleep, intermittent fasting or even prolonged starvation requires complex metabolic adaptations [1–3].
Multi-drug approaches to NASH: what’s in the development pipeline?
Published in Expert Opinion on Investigational Drugs, 2020
Michael P Johnston, Janisha Patel, Christopher D Byrne
Fatty infiltration of the liver (hepatic steatosis) may be isolated or progress to an inflammatory process of hepatocyte ballooning and lobular inflammation. Manipulation of fatty acid metabolism through an array of mechanisms is a promising strategy for abating this pathological process. Although incompletely understood, targeting bile acid synthesis is one approach that directly influences cholesterol metabolism and benefits NASH. NGM-282 is an analog of fibroblast growth factor 19 (FGF-19) which has been studied in a phase II trial of patients with a histological diagnosis of NASH. Patients who received NGM-282 achieved 58% and 67% relative reduction in liver fat at 12 weeks at low and high doses, respectively [8]. In addition to its effect on steatosis, NGM-282 significantly improved fibrosis score by ≥1 point, without worsening of steatohepatitis.
Effects of Docosahexaenoic Acid on Chemokine Expression in Human Conjunctival Fibroblasts
Published in Current Eye Research, 2020
Hiroyuki Yazu, Kazumi Fukagawa, Naoko Okada, Hiroshi Fujishima
In fatty acid metabolism, various biologically active substances are produced from AA and EPA. These are called eicosanoids and include PG, thromboxane, and LT. Eicosanoids derived from ω-6 fatty acids cause hypervascular permeability, induce and activate neutrophils, promote the production of inflammatory cytokines in inflammation, and act on pro-inflammatory responses. In contrast, eicosanoids derived from ω-3 fatty acids act to suppress inflammation, exerting anti-inflammatory, vascular protective, and inhibitory effects on inflammatory cytokine production. At the molecular level, the mechanism of action involves suppression of the production and function of pro-inflammatory eicosanoids because the metabolic pathway in which eicosanoids are produced from ω-3 fatty acids acts by competitive inhibition of these of ω-6 fatty acids. However, the presence of a lipid mediator with anti-inflammatory activity was revealed. For example, resolvin E1, which is biosynthesized from EPA, and protectin D1,20 which is biosynthesized from DHA, exhibit anti-inflammatory effects, even when present in small amounts,21,22 and are believed to be produced by an intercellular biosynthetic pathway involving localization of inflammation. Moreover, Shimanaka et al. reported that substantial levels of epoxyeicosatetraenoic acids derived from ω-3 fatty acids enhance mast cell activation and anaphylaxis in animals.23
Related Knowledge Centers
- Anabolism
- Beta Oxidation
- Fatty Acid
- Metabolism
- Catabolism
- Citric Acid Cycle
- Lipid
- Triglyceride
- Nutrient
- Adenosine Triphosphate