Upregulation of Fatty Acyl-CoA Thioesterases in the Heart and Skeletal Muscle of Rats Fed a High-Fat Diet

Abstract

Over the past few decades, the prevalence of overweight and obesity has increased markedly worldwide, along with the adoption of westernized lifestyles characterized by excessive energy intake and a lack of physical activity. Consequently, obesity and a cluster of obesity-related comorbidities often referred to as the metabolic syndrome have become a serious public health problem and a major risk factor for the development of severe diseases such as cardiovascular disease. 1) Obesity is strongly associated with insulin resistance, in which elevation of circulating fatty acids results in increased fatty acid availability that exceeds the fat disposal capacity of cells, which decreases insulin-stimulated glucose oxidation in muscles and subsequently leads to contractile dysfunction of the heart. 2) The precise mechanisms underlying these "lipotoxic" consequences remain incompletely defined, but it is currently accepted that excessive fatty acid uptake into cells leads to the accumulation of proinflammatory lipid metabolites such as fatty acyl-CoA, diacylglycerol and ceramide. These metabolites stimulate stress-activated kinases, which interfere with insulin signaling. 2,3) It is also becoming clear that fatty acid beta-oxidation is increased in the insulin-resistant heart and oxidative skeletal muscle, and that mitochondrial overload and incomplete oxidation of fatty acids contribute to the impairment of insulin sensitivity. 2,4) Under these conditions, enhanced beta-oxidation, which is not accompanied by appropriate upregulation of the tricarboxylic acid (TCA) cycle or electron transport chain (ETC) activity, fails to oxidize fatty acids completely to CO 2 and deposits incomplete fat catabolites along with diminished levels of TCA cycle intermediates. These stressful environments created within mitochondria are thought to exacerbate cellular insulin resistance by enhanced oxidative stress, for example. 4) However, acyl-CoA thioesterase (ACOT) exists within the mitochondrial matrix of mammalian cells 5) and its expression is expected to be upregulated in response to fatty acid overload, as demonstrated in diabetic and fasted animals. 6,7) ACOT comprises a group of enzymes that are localized in multiple compartments in cells and catalyze the hydrolysis of long-chain acyl-CoA thioesters to free fatty acids and CoA-SH. For example, ACOT1 (formerly known as CTE-I or ACH2) and ACOT7a (CTE-II, BACH or ACT) are localized in the cytosol while ACOT2 (MTE-I or ARTISt) and ACOT7b (MTE-II or LACH1) are present in mitochondria. [8][9][10] These catalytic properties of ACOT mean that it is capable of lowering the increased levels of acyl-CoA imported by carnitine palmitoyltransferase (CPT) across the mitochondrial membranes from the cytosol. Accordingly, ACOT could counteract the enhanced beta-oxidation and reduce the mitochondrial stress caused by the imbalance between beta-oxidation and TCA cycle/ETC activity during fatty acid overload. Moreover, the ACOT isoforms present in the cytosol could scavenge surplus acyl-CoA to prev...

Dietary fatty acids alter left ventricular myocardial gene expression in Wistar rats

“…[59] The isozyme, ACOT1, is localized to the cytosol and regulated by PPAR-α. [60] ACOT1 is increased in the myocardium of rats fed a high-fat diet,[60, 61] an effect proposed to attenuate aberrant mitochondrial fatty acid oxidation and mitochondrial stress, thus preserving contractile function. [61] Myocardial Acot1 and other fatty acid-responsive genes were increased to a lesser extent in Western diet-fed rats compared to high-fat fed animals, to which attenuated fatty acid oxidation and contractile dysfunction were attributed.…”

“…[60] ACOT1 is increased in the myocardium of rats fed a high-fat diet,[60, 61] an effect proposed to attenuate aberrant mitochondrial fatty acid oxidation and mitochondrial stress, thus preserving contractile function. [61] Myocardial Acot1 and other fatty acid-responsive genes were increased to a lesser extent in Western diet-fed rats compared to high-fat fed animals, to which attenuated fatty acid oxidation and contractile dysfunction were attributed. [62] Expression of myocardial Acot1 is partly determined by ingested fatty acids, demonstrated in a study detailing the effect of a single dose of isolated fatty acids in mice.…”

Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation

“…For example, the biosynthesis of fatty acids was up-regulated as was also indicated by single gene analysis (Table I). Indeed, acyl-CoA thioesterase 7 (ACOT7), which catalyzes the hydrolysis of long-chain acyl-CoA thioesters to free fatty acids and coenzyme A (Fujita et al 2011) was upregulated after one week of exposure to 4.1 mGy/h (FC 1.54). Likewise, perilipin 3 (PLIN3) (FC 1.53) was up-regulated, which is, as a carrier protein of free fatty acids, involved in lipid droplet formation, stabilization and functioning (Buers et al 2011).…”

Identification of Acyl-CoA Thioesterase in Mouse Mesenteric Lymph Nodes

“…8,[11][12][13]16) It should be noted that the anti-ACOT1 antibody cross-reacts with ACOT2. Immunoglobulin (Ig) G was prepared from antisera using protein A sepharose (Ge Healthcare, Buckinghamshire, U.K.).…”

“…Moreover, ACOT1 and ACOT2 have been implicated in fatty acid catabolism, as emphasized by their upregulation in the liver and heart of fasted or high-fat diet-fed animals. [8][9][10][11] However, ACOT7 has enzyme activity two orders of magnitude higher than ACOT1 and ACOT2, and its expression is prominent in neurons of the central and peripheral nervous systems. [12][13][14] Thus, ACOT7 may have a role in cellular events other than energy metabolism, as the overexpression of ACOT7 in a macrophage cell line modified the production of prostaglandins.…”