scholarly journals High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta

2013 ◽  
Vol 305 (2) ◽  
pp. E205-E212 ◽  
Author(s):  
Francisco Visiedo ◽  
Fernando Bugatto ◽  
Viviana Sánchez ◽  
Irene Cózar-Castellano ◽  
Jose L. Bartha ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Glucose ◽  
De Novo ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Glucose Levels ◽  
Triglyceride Accumulation ◽  
Triglyceride Content ◽  
Low Glucose ◽  
Cpt I

Placentas of women with gestational diabetes mellitus (GDM) exhibit an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high glucose levels reduce mitochondrial fatty acid oxidation (FAO) and increase triglyceride accumulation in human placenta. To test this hypothesis, we measured FAO, fatty acid esterification, de novo fatty acid synthesis, triglyceride levels, and carnitine palmitoyltransferase activities (CPT) in placental explants of women with GDM or no pregnancy complication. In women with GDM, FAO was reduced by ∼30% without change in mitochondrial content, and triglyceride content was threefold higher than in the control group. Likewise, in placental explants of women with no complications, high glucose levels reduced FAO by ∼20%, and esterification increased linearly with increasing fatty acid concentrations. However, de novo fatty acid synthesis remained unchanged between high and low glucose levels. In addition, high glucose levels increased triglyceride content approximately twofold compared with low glucose levels. Furthermore, etomoxir-mediated inhibition of FAO enhanced esterification capacity by ∼40% and elevated triglyceride content 1.5-fold in placental explants of women, with no complications. Finally, high glucose levels reduced CPT I activity by ∼70% and phosphorylation levels of acetyl-CoA carboxylase by ∼25% in placental explants of women, with no complications. We reveal an unrecognized regulatory mechanism on placental fatty acid metabolism by which high glucose levels reduce mitochondrial FAO through inhibition of CPT I, shifting flux of fatty acids away from oxidation toward the esterification pathway, leading to accumulation of placental triglycerides.

Effects of extracellular ATP on hepatic fatty acid metabolism

1996 ◽  
Vol 270 (4) ◽  
pp. G701-G707 ◽  
Author(s):  
M. Guzman ◽  
G. Velasco ◽  
J. Castro
Keyword(s):  
Fatty Acid ◽  
De Novo ◽  
Specific Inhibitor ◽  
Rat Hepatocytes ◽  
Inhibitory Effect ◽  
Extracellular Atp ◽  
Acid Oxidation ◽  
A 23187 ◽  
Malonyl Coa ◽  
Cpt I

Incubation of rat hepatocytes with extracellular ATP inhibited acetyl-CoA carboxylase (ACC) activity and fatty acid synthesis de novo, with a concomitant decrease of intracellular malonyl-CoA concentration. However, both carnitine O-palmitoyltransferase I (CPT-I) activity and ketogenesis from palmitate were inhibited in parallel by extracellular ATP. The inhibitory effect of extracellular ATP on ACC and CPT-I activities was not evident in Ca2+ -depleted hepatocytes. Incubation of hepatocytes with thapsigargin, 2,5-di-(t-butyl)-1,4-benzohydroquinone (BHQ), or A-23187, compounds that increase cytosolic free Ca2+ concentration ([Ca2+]i), depressed ACC activity, whereas CPT-I activity was unaffected. The phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) increased ACC activity, whereas it decreased CPT-I activity in a nonaddictive manner with respect to extracellular ATP. The inhibitory effect of extracellular ATP on ACC activity was also evident in the presence of bisindolyl-maleimide, a specific inhibitor of protein kinase C (PKC), whereas this compound abolished the extracellular ATP-mediated inhibition of CPT-I. In addition, the PMA-induced inhibition of CPT-I was not potentiated by thapsigargin, BHQ, or A-23187. Results thus show 1) that the intracellular concentration of malonyl-CoA is not the factor responsible for the inhibition of hepatic long-chain fatty acid oxidation by extracellular ATP, and 2) that the inhibition of ACC by extracellular ATP may be mediated by an elevation of [Ca2+]i, whereas CPT-I may be inhibited by extracellular ATP through a PKC-dependent mechanism.

scholarly journals Inhibition of Atherosclerosis and Liver Steatosis by Agmatine in Western Diet-Fed apoE-Knockout Mice Is Associated with Decrease in Hepatic De Novo Lipogenesis and Reduction in Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio

2021 ◽  
Vol 22 (19) ◽  
pp. 10688
Author(s):  
Anna Wiśniewska ◽  
Aneta Stachowicz ◽  
Katarzyna Kuś ◽  
Magdalena Ulatowska-Białas ◽  
Justyna Totoń-Żurańska ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hepatic Steatosis ◽  
De Novo ◽  
Therapeutic Potential ◽  
Liver Steatosis ◽  
Western Diet ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Cholesterol Ratio ◽  
Triglyceride Accumulation

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE−/− mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE−/− mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study.

scholarly journals Cardiomyocyte Triglyceride Accumulation and Reduced Ventricular Function in Mice with Obesity Reflect Increased Long Chain Fatty Acid Uptake andDe NovoFatty Acid Synthesis

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Fengxia Ge ◽  
Chunguang Hu ◽  
Eiichi Hyodo ◽  
Kotaro Arai ◽  
Shengli Zhou ◽  
...  
Keyword(s):  
Fatty Acid ◽  
De Novo ◽  
Contractile Function ◽  
Atp Synthesis ◽  
Acid Synthesis ◽  
Fatty Acid Uptake ◽  
Left Ventricular ◽  
Acid Uptake ◽  
Triglyceride Accumulation ◽  
Oxidative Phosphorylation Pathway

A nonarteriosclerotic cardiomyopathy is increasingly seen in obese patients. Seeking a rodent model, we studied cardiac histology, function, cardiomyocyte fatty acid uptake, and transporter gene expression in male C57BL/6J control mice and three obesity groups: similar mice fed a high-fat diet (HFD) anddb/dbandob/obmice. At sacrifice, all obesity groups had increased body and heart weights and fatty livers. By echocardiography, ejection fraction (EF) and fractional shortening (FS) of left ventricular diameter during systole were significantly reduced. TheVmaxfor saturable fatty acid uptake was increased and significantly correlated with cardiac triglycerides and insulin concentrations.Vmaxalso correlated with expression of genes for the cardiac fatty acid transportersCd36andSlc27a1. Genes forde novofatty acid synthesis (Fasn, Scd1) were also upregulated. Ten oxidative phosphorylation pathway genes were downregulated, suggesting that a decrease in cardiomyocyte ATP synthesis might explain the decreased contractile function in obese hearts.

scholarly journals The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2600
Author(s):  
Matheus Pinto De Oliveira ◽  
Marc Liesa
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Cancer Proliferation

Tumors remodel their metabolism to support anabolic processes needed for replication, as well as to survive nutrient scarcity and oxidative stress imposed by their changing environment. In most healthy tissues, the shift from anabolism to catabolism results in decreased glycolysis and elevated fatty acid oxidation (FAO). This change in the nutrient selected for oxidation is regulated by the glucose-fatty acid cycle, also known as the Randle cycle. Briefly, this cycle consists of a decrease in glycolysis caused by increased mitochondrial FAO in muscle as a result of elevated extracellular fatty acid availability. Closing the cycle, increased glycolysis in response to elevated extracellular glucose availability causes a decrease in mitochondrial FAO. This competition between glycolysis and FAO and its relationship with anabolism and catabolism is conserved in some cancers. Accordingly, decreasing glycolysis to lactate, even by diverting pyruvate to mitochondria, can stop proliferation. Moreover, colorectal cancer cells can effectively shift to FAO to survive both glucose restriction and increases in oxidative stress at the expense of decreasing anabolism. However, a subset of B-cell lymphomas and other cancers require a concurrent increase in mitochondrial FAO and glycolysis to support anabolism and proliferation, thus escaping the competing nature of the Randle cycle. How mitochondria are remodeled in these FAO-dependent lymphomas to preferably oxidize fat, while concurrently sustaining high glycolysis and increasing de novo fatty acid synthesis is unclear. Here, we review studies focusing on the role of mitochondrial FAO and mitochondrial-driven lipid synthesis in cancer proliferation and survival, specifically in colorectal cancer and lymphomas. We conclude that a specific metabolic liability of these FAO-dependent cancers could be a unique remodeling of mitochondrial function that licenses elevated FAO concurrent to high glycolysis and fatty acid synthesis. In addition, blocking this mitochondrial remodeling could selectively stop growth of tumors that shifted to mitochondrial FAO to survive oxidative stress and nutrient scarcity.

scholarly journals Prostate Cancer Proliferation Is Affected by the Subcellular Localization of MCT2 and Accompanied by Significant Peroxisomal Alterations

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3152
Author(s):  
Isabel Valença ◽  
Ana Rita Ferreira ◽  
Marcelo Correia ◽  
Sandra Kühl ◽  
Carlo van Roermund ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
De Novo ◽  
Redox Balance ◽  
Acid Synthesis ◽  
Monocarboxylate Transporter ◽  
Acid Oxidation ◽  
Cellular Mechanisms ◽  
Oxidation Rates

Reprogramming of lipid metabolism directly contributes to malignant transformation and progression. The increased uptake of circulating lipids, the transfer of fatty acids from stromal adipocytes to cancer cells, the de novo fatty acid synthesis, and the fatty acid oxidation support the central role of lipids in many cancers, including prostate cancer (PCa). Fatty acid β-oxidation is the dominant bioenergetic pathway in PCa and recent evidence suggests that PCa takes advantage of the peroxisome transport machinery to target monocarboxylate transporter 2 (MCT2) to peroxisomes in order to increase β-oxidation rates and maintain the redox balance. Here we show evidence suggesting that PCa streamlines peroxisome metabolism by upregulating distinct pathways involved in lipid metabolism. Moreover, we show that MCT2 is required for PCa cell proliferation and, importantly, that its specific localization at the peroxisomal membranes is essential for this role. Our results highlight the importance of peroxisomes in PCa development and uncover different cellular mechanisms that may be further explored as possible targets for PCa therapy.

scholarly journals Exercise and Omega-3 Polyunsaturated Fatty Acid Supplementation for the Treatment of Hepatic Steatosis in Hyperphagic OLETF Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Sarah J. Borengasser ◽  
R. Scott Rector ◽  
Grace M. Uptergrove ◽  
E. Matthew Morris ◽  
James W. Perfield ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Omega 3 ◽  
Oletf Rats ◽  
Hepatic Fatty Acid

Background and Aims.This study examined if exercise and omega-3 fatty acid (n3PUFA) supplementation is an effective treatment for hepatic steatosis in obese, hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats.Methods.Male OLETF rats were divided into 4 groups (n=8/group): (1) remained sedentary (SED), (2) access to running wheels; (EX) (3) a diet supplemented with 3% of energy from fish oil (n3PUFA-SED); and (4) n3PUFA supplementation plus EX (n3PUFA+EX). The 8 week treatments began at 13 weeks, when hepatic steatosis is present in OLETF-SED rats.Results.EX alone lowered hepatic triglyceride (TAG) while, in contrast, n3PUFAs failed to lower hepatic TAG and blunted the ability of EX to decrease hepatic TAG levels in n3PUFAs+EX. Insulin sensitivity was improved in EX animals, to a lesser extent in n3PUFA+EX rats, and did not differ between n3PUFA-SED and SED rats. Only the EX group displayed higher complete hepatic fatty acid oxidation (FAO) to CO2and carnitine palmitoyl transferase-1 activity. EX also lowered hepatic fatty acid synthase protein while both EX and n3PUFA+EX decreased stearoyl CoA desaturase-1 protein.Conclusions.Exercise lowers hepatic steatosis through increased complete hepatic FAO, insulin sensitivity, and reduced expression ofde novofatty acid synthesis proteins while n3PUFAs had no effect.

Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys

1998 ◽  
Vol 274 (2) ◽  
pp. R524-R528 ◽  
Author(s):  
Rhonda O. Deems ◽  
Robert C. Anderson ◽  
James E. Foley
Keyword(s):  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Fatty Acid Oxidation ◽  
Hypoglycemic Agents ◽  
Dependent Diabetes Mellitus ◽  
Reversible Inhibitor ◽  
Acid Oxidation ◽  
Glucose Lowering ◽  
Glucose Levels ◽  
Cpt I

Increased fatty acid oxidation contributes to hyperglycemia in patients with non-insulin-dependent diabetes mellitus. To improve glucose homeostasis in these patients, we have designed a novel, reversible inhibitor of carnitine palmitoyltransferase I (CPT I) that potently inhibits fatty acid oxidation. SDZ-CPI-975 significantly lowered glucose levels in normal 18-h-fasted nonhuman primates and rats. In rats, glucose lowering required fatty acid oxidation inhibition of ≥70%, as measured by β-hydroxybutyrate levels, the end product of β-oxidation. In cynomolgus monkeys, comparable glucose lowering was achieved with more modest lowering of β-hydroxybutyrate levels. SDZ-CPI-975 did not increase glucose utilization by heart muscle, suggesting that CPT I inhibition with SDZ-CPI-975 would not induce cardiac hypertrophy. This was in contrast to the irreversible CPT I inhibitor etomoxir. These results demonstrate that SDZ-CPI-975 effectively inhibited fatty acid oxidation and lowered blood glucose levels in two species. Thus reversible inhibitors of CPT I represent a class of novel hypoglycemic agents that inhibit fatty acid oxidation without inducing cardiac hypertrophy.

Contribution of malonyl-CoA decarboxylase to the high fatty acid oxidation rates seen in the diabetic heart

2000 ◽  
Vol 278 (4) ◽  
pp. H1196-H1204 ◽  
Author(s):  
Jun Sakamoto ◽  
Rick L. Barr ◽  
Katherine M. Kavanagh ◽  
Gary D. Lopaschuk
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
High Glucose ◽  
Glucose Oxidation ◽  
High Fatty Acid ◽  
Acid Oxidation ◽  
High Fat ◽  
Low Fat ◽  
Oxidation Rates ◽  
Low Glucose

Myocardial glucose oxidation is markedly reduced in the uncontrolled diabetic. We determined whether this was due to direct biochemical changes in the heart or whether this was due to altered circulating levels of insulin and substrates that can be seen in the diabetic. Isolated working hearts from control or diabetic rats (streptozotocin, 55 mg/kg iv administered 6 wk before study) were aerobically perfused with either 5 mM [14C]glucose and 0.4 mM [3H]palmitate (low-fat/low-glucose buffer) or 20 mM [14C]glucose and 1.2 mM [3H]palmitate (high-fat/high-glucose buffer) ±100 μU/ml insulin. The presence of insulin increased glucose oxidation in control hearts perfused with low-fat/low-glucose buffer from 553 ± 85 to 1,150 ± 147 nmol ⋅ g dry wt−1 ⋅ min−1( P < 0.05). If control hearts were perfused with high-fat/high-glucose buffer, palmitate oxidation was significantly increased by 112% ( P < 0.05), but glucose oxidation decreased to 55% of values seen in the low-fat/low-glucose group ( P < 0.05). In diabetic hearts, glucose oxidation was very low in hearts perfused with low-fat/low-glucose buffer (9 ± 1 nmol ⋅ g dry wt−1 ⋅ min−1) and was not altered by insulin or high-fat/high-glucose buffer. These results suggest that neither circulating levels of substrates nor insulin was responsible for the reduced glucose oxidation in diabetic hearts. To determine if subcellular changes in the control of fatty acid oxidation contribute to these changes, we measured the activity of three enzymes involved in the control of fatty acid oxidation; AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and malonyl-CoA decarboxylase (MCD). Although AMPK and ACC activity in control and diabetic hearts was not different, MCD activity and expression in all diabetic rat heart perfusion groups were significantly higher than that seen in corresponding control hearts. These results suggest that an increased MCD activity contributes to the high fatty acid oxidation rates and reduced glucose oxidation rates seen in diabetic rat hearts.

scholarly journals The Lipid Metabolic Landscape of Cancers and New Therapeutic Perspectives

2020 ◽  
Vol 10 ◽  
Author(s):  
Wenjun Wang ◽  
Ling Bai ◽  
Wei Li ◽  
Jiuwei Cui
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Tumor Growth ◽  
Cancer Patients ◽  
De Novo ◽  
Tumor Therapy ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Lipid Uptake ◽  
Oncogenic Signaling

Lipid metabolism reprograming, as a hallmark of malignancy, has received renewed interest in recent years in such areas as energy sources, cell membrane components, and signaling molecules involved in the rapid tumor growth and the adaptation to the tumor microenvironment. Lipid metabolism deregulation in cancer involves multiple aspects, including an increased lipid uptake, endogenous de novo fatty acid synthesis, fatty acid oxidation, and cholesterol accumulation, thereby promoting tumor growth and progression. Recent advances in the understanding of specific metabolic alterations in cancer reveal novel pathogenesis mechanisms and a growing number of drugs targeting lipid metabolism have been applied in anti-tumor therapy. Thus, this review discusses the lipid metabolic landscape of cancers and the interplay with oncogenic signaling, and summarizes potential therapeutic targets to improve the therapeutic efficiency in cancer patients, in order to provide more reference and thinking for the treatment of lipid metabolism of cancer patients.

scholarly journals Targeted induction of de novo Fatty acid synthesis enhances MDV replication in a COX-2/PGE2α dependent mechanism through EP2 and EP4 receptors engagement

2018 ◽  
Author(s):  
Nitish Boodhoo ◽  
Nitin Kamble ◽  
Benedikt B. Kaufer ◽  
Shahriar Behboudi
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Virus Replication ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Particle Assembly ◽  
Infected Cells ◽  
Cox 2

AbstractMany viruses alter de novo Fatty Acid (FA) synthesis pathway, which can increase availability of energy for replication and provide specific cellular substrates for particle assembly. Marek’s disease virus (MDV) is a herpesvirus that causes deadly lymphoma and has been linked to alterations of lipid metabolism in MDV-infected chickens. However, the role of lipid metabolism in MDV replication is largely unknown. We demonstrate here that infection of primary chicken embryonic fibroblast with MDV activates de novo lipogenesis, which is required for virus replication. In contrast, activation of Fatty Acid Oxidation (FAO) reduced MDV titer, while inhibition of FAO moderately increased virus replication. Thus optimized virus replication occurs if synthetized fatty acids are not used for generation of energy in the infected cells, and they are likely converted to lipid compounds, which are important for virus replication. We showed that infection with MDV activates COX-2/PGE2α pathway and increases the biosynthesis of PGE2α, a lipid mediator generated from arachidonic acid. Inhibition of COX-2 or PGE2α receptors, namely EP2 and EP4 receptors, reduced MDV titer, indicating that COX-2/PGE2α pathway are involved in virus replication. Our data show that the FA synthesis pathway inhibitors reduce COX-2 expression level and PGE2α synthesis in MDV infected cells, arguing that there is a direct link between virus-induced fatty acid synthesis and activation of COX-2/PGE2α pathway. This notion was confirmed by the results showing that PGE2α can restore MDV replication in the presence of the FA synthesis pathway inhibitors. Taken together, our data demonstrate that MDV uses FA synthesis pathway to enhance PGE2α synthesis and promote MDV replication through EP2 and EP4 receptors engagement.

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