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Free Fatty Acids: Circulating Contributors of Metabolic Syndrome.
Suiter, C, Singha, SK, Khalili, R, Shariat-Madar, Z
Cardiovascular & hematological agents in medicinal chemistry. 2018;(1):20-34
Abstract
Metabolic syndrome induces an increased cardiovascular morbidity and mortality. Most importantly, the prevalence of metabolic syndrome in adult population is expanding. Both clinical and preclinical studies indicate that increased Free Fatty Acids (FFAs) are involved in the pathogenesis of insulin resistance and subsequent development of metabolic syndrome. The relevance of FFAs in protecting and restoring tissue function is quite vast. The search to correlate the functional deterioration of the tissues within the cardiovascular system and increased plasma concentrations of FFAs has been reported. The importance of reduction in the consumption of dietary fatty acids along with the identification of dysregulated genes responsible for persistent increased FFAs uptake and mitochondrial β-oxidation has been increasingly recognized. This review discusses the current empirical understanding of the different types of fatty acids and their metabolism and functions both in physiological and pathophysiological conditions. We also discuss in detail about the molecular and pathophysiological basis of increased FFAs, which augments Cardiovascular Disease (CVD).
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2.
El papel de los ácidos grasos libres en la resistencia a la insulina.
Vázquez-Jiménez, JG, Roura-Guiberna, A, Jiménez-Mena, LR, Olivares-Reyes, JA
Gaceta medica de Mexico. 2017;(7):852-863
Abstract
Free fatty acids are essential nutritional components and recent studies identified them as signaling molecules in various physiological processes. It has now been shown that high levels of free fatty acids, particularly saturated fatty acids, may be associated with insulin resistance in obese patients with type 2 diabetes mellitus. Insulin resistance is important in clinical since it is related to various diseases including type 2 diabetes mellitus, dyslipidemia, and abnormalities at cardiovascular level. Recent studies have proposed different molecular mechanisms by which these lipids may alter the signaling pathway of insulin. The purpose of this review is to highlight recent advances in the study of the effect of free fatty acids as modulators of insulin response.
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3.
Acidemia and blood free fatty acids: analysis of cardiovascular risk factors in a new context.
Reis, AH
Discovery medicine. 2017;(126):183-188
Abstract
Following a hypothesis developed in an earlier paper, here it is discussed how deviations of blood pH from the normal range (namely states of acidemia) together with high blood levels of free fatty acids (FFA) may offer a rationale for many important risk factors for cardiovascular diseases (CVD) by shaping a context for formation of fatty acid micelles and vesicles with an acidic core, which fuse with the endothelia, disrupt vital cell processes, and thereby may initiate atherosclerotic plaque formation. Acidemia may arise primarily from dysregulation of the systemic buffers that control blood pH, chronic diseases of kidneys and lungs, inappropriate diet, or may be induced by some common drugs. The level of free fatty acids may be increased and maintained high by chronic stress, and adrenergic shocks. Elevated concentrations of blood FFA in a context of acidemia allow to understand important cardiovascular aspects: the increased risk of menopausal women, the protective effects of physical exercise, the changes in vascular behavior characteristic of metabolic acidosis/acidemia, the role of diet in the pH balance, on how some known medicines like metformin, steroids, NSAIDS, proton pump inhibitors, and calcium supplements may influence CVD risk, and an explanation is offered for the role of statins.
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4.
Targeting fatty acid metabolism to improve glucose metabolism.
Stinkens, R, Goossens, GH, Jocken, JW, Blaak, EE
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2015;(9):715-57
Abstract
Disturbances in fatty acid metabolism in adipose tissue, liver, skeletal muscle, gut and pancreas play an important role in the development of insulin resistance, impaired glucose metabolism and type 2 diabetes mellitus. Alterations in diet composition may contribute to prevent and/or reverse these disturbances through modulation of fatty acid metabolism. Besides an increased fat mass, adipose tissue dysfunction, characterized by an altered capacity to store lipids and an altered secretion of adipokines, may result in lipid overflow, systemic inflammation and excessive lipid accumulation in non-adipose tissues like liver, skeletal muscle and the pancreas. These impairments together promote the development of impaired glucose metabolism, insulin resistance and type 2 diabetes mellitus. Furthermore, intrinsic functional impairments in either of these organs may contribute to lipotoxicity and insulin resistance. The present review provides an overview of fatty acid metabolism-related pathways in adipose tissue, liver, skeletal muscle, pancreas and gut, which can be targeted by diet or food components, thereby improving glucose metabolism.
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5.
[Free Fatty Acid Receptor Family: A New Therapeutic Target for Metabolic Diseases].
Hirasawa, A
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2015;(6):769-77
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Abstract
Free fatty acids (FFAs) are not only essential nutritional components but they also act as signaling molecules in various physiological processes. A strategy to deorphanize G-protein-coupled receptors (GPCRs) identified a series of receptors for FFAs that play significant roles in nutrition regulation. In this free fatty acid receptor family, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain FFAs. FFAR1 regulates insulin secretion in pancreatic β-cells, whereas FFAR4 promotes the secretion of glucagon-like peptide-1 (GLP-1) in the intestine, and also acts as a lipid sensor in adipose tissue to sense dietary fat and control energy balance. In this review, we discuss recent advances in the pharmacological characterization of FFAR1 and FFAR4, and we present a summary of current understandings of their physiological roles and their potential as drug targets.
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6.
Role of free fatty acid receptors in the regulation of energy metabolism.
Hara, T, Kashihara, D, Ichimura, A, Kimura, I, Tsujimoto, G, Hirasawa, A
Biochimica et biophysica acta. 2014;(9):1292-300
Abstract
Free fatty acids (FFAs) are energy-generating nutrients that act as signaling molecules in various cellular processes. Several orphan G protein-coupled receptors (GPCRs) that act as FFA receptors (FFARs) have been identified and play important physiological roles in various diseases. FFA ligands are obtained from food sources and metabolites produced during digestion and lipase degradation of triglyceride stores. FFARs can be grouped according to ligand profiles, depending on the length of carbon chains of the FFAs. Medium- and long-chain FFAs activate FFA1/GPR40 and FFA4/GPR120. Short-chain FFAs activate FFA2/GPR43 and FFA3/GPR41. However, only medium-chain FFAs, and not long-chain FFAs, activate GPR84 receptor. A number of pharmacological and physiological studies have shown that these receptors are expressed in various tissues and are primarily involved in energy metabolism. Because an impairment of these processes is a part of the pathology of obesity and type 2 diabetes, FFARs are considered as key therapeutic targets. Here, we reviewed recently published studies on the physiological functions of these receptors, primarily focusing on energy homeostasis.
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Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes.
Legrand-Poels, S, Esser, N, L'homme, L, Scheen, A, Paquot, N, Piette, J
Biochemical pharmacology. 2014;(1):131-41
Abstract
Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet or synthesized endogenously. In addition to serving as an important source of energy, they produce a variety of both beneficial and detrimental effects. They play essential roles as structural components of all cell membranes and as signaling molecules regulating metabolic pathways through binding to nuclear or membrane receptors. However, under conditions of FFAs overload, they become toxic, inducing ROS production, ER stress, apoptosis and inflammation. SFAs (saturated fatty acids), unlike UFAs (unsaturated fatty acids), have recently been proposed as triggers of the NLRP3 inflammasome, a molecular platform mediating the processing of IL-1β in response to infection and stress conditions. Interestingly, UFAs, especially ω-3 FAs, inhibit NLRP3 inflammasome activation in various settings. We focus on emerging models of NLRP3 inflammasome activation with a special emphasis on the molecular mechanisms by which FFAs modulate the activation of this complex. Taking into consideration the current literature and FFA properties, we discuss the putative involvement of mitochondria and the role of cardiolipin, a mitochondrial phospholipid, proposed to be sensed by NLRP3 after release, exposure and/or oxidation. Finally, we review how this SFA-mediated NLRP3 inflammasome activation contributes to the development of both insulin resistance and deficiency associated with obesity/type 2 diabetes. In this context, we highlight the potential clinical use of ω-3 FAs as anti-inflammatory compounds.
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8.
Lipid metabolites and their differential pro-arrhythmic profiles: of importance in the development of a new anti-arrhythmic pharmacology.
Shao, Y, Redfors, B, Benoist, D, Gizurarson, S, Omerovic, E
Molecular and cellular biochemistry. 2014;(1-2):191-7
Abstract
Arrhythmias have been treated for a long time with drugs that mainly target the ionic pumps and channels. These anti-arrhythmic regimens per se introduce new arrhythmias, which can be detrimental to patients. Advances in development of novel pharmacology without introduction of iatrogenic arrhythmias are thus favorable for an effective treatment of arrhythmias. Electrophysiological stability of the heart has been shown to be closely associated with cardiac metabolism. The present effective anti-arrhythmic drugs such as beta-blockers and amiodarone have profound beneficial effects in regulating myocardial metabolism. Aiming at decreasing production of toxic metabolites or preventing accumulation of arrhythmogenic lipids perhaps is a good strategy to effectively control arrhythmias. Therefore, a better understanding of the pro-arrhythmic profiles of cardiac metabolites helps to explore a new generation of metabolically oriented anti-arrhythmic medications. In this review, we present several lipid metabolites and summarize their arrhythmogenic characteristics.
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9.
Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease.
Gaggini, M, Morelli, M, Buzzigoli, E, DeFronzo, RA, Bugianesi, E, Gastaldelli, A
Nutrients. 2013;(5):1544-60
Abstract
Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease.
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10.
[Progress in the structure and function of human carboxylesterase 1].
Tong, J, Yi, Y, Cao, P, Liu, C, Wang, L, Lü, Y
Sheng wu gong cheng xue bao = Chinese journal of biotechnology. 2012;(12):1414-22
Abstract
Human carboxylesterase 1 (HCE1), belonging to a multigene serine hydrolase family, is a major liver carboxylesterase responsible for the hydrolysis and metabolism of various xenobiotics. It also plays an important role in the transportation and metabolism of endogenous cholesterol ester and free fatty acid, and is closely associated with the pathogenesis of hepatocellular carcinoma. This review describes current developments in the molecular structure, the roles in drug, toxins and lipid metabolism, and the early diagnosis for hepatocellular carcinoma of human carboxylesterase 1.