scholarly journals Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer

2019 ◽  
Vol 133 (15) ◽  
pp. 1745-1758 ◽  
Author(s):  
Songtao Cheng ◽  
Gang Wang ◽  
Yejinpeng Wang ◽  
Liwei Cai ◽  
Kaiyu Qian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Fatty Acid ◽  
Tumor Progression ◽  
Cell Cycle Arrest ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Cycle Arrest

Abstract Tumor cells rely on aerobic glycolysis as their main energy resource (Warburg effect). Recent research has highlighted the importance of lipid metabolism in tumor progression, and certain cancers even turn to fatty acids as the main fuel. Related studies have identified alterations of fatty acid metabolism in human bladder cancer (BCa). Our microarray analysis showed that fatty acid metabolism was activated in BCa compared with normal bladder. The free fatty acid (FFA) level was also increased in BCa compared with paracancerous tissues. Inhibition of fatty acid oxidation (FAO) with etomoxir caused lipid accumulation, decreased adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, suppressed BCa cell growth in vitro and in vivo, and reduced motility of BCa cells via affecting epithelial–mesenchymal transition (EMT)-related proteins. Furthermore, etomoxir induced BCa cell cycle arrest at G0/G1 phase through peroxisome proliferator-activated receptor (PPAR) γ-mediated pathway with alterations in fatty acid metabolism associated gene expression. The cell cycle arrest could be reversed by PPARγ antagonist GW9662. Taken together, our results suggest that inhibition of FAO with etomoxir may provide a novel avenue to investigate new therapeutic approaches to human BCa.

Effect of hyperglycemia-hyperinsulinemia on whole body and regional fatty acid metabolism

1999 ◽  
Vol 276 (3) ◽  
pp. E427-E434 ◽  
Author(s):  
Labros S. Sidossis ◽  
Bettina Mittendorfer ◽  
David Chinkes ◽  
Eric Walser ◽  
Robert R. Wolfe
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Fatty Acid Uptake ◽  
Whole Body ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Similar Extent ◽  
Body Level

The effects of combined hyperglycemia-hyperinsulinemia on whole body, splanchnic, and leg fatty acid metabolism were determined in five volunteers. Catheters were placed in a femoral artery and vein and a hepatic vein. U-13C-labeled fatty acids were infused, once in the basal state and, on a different occasion, during infusion of dextrose (clamp; arterial glucose 8.8 ± 0.5 mmol/l). Lipids and heparin were infused together with the dextrose to maintain plasma fatty acid concentrations at basal levels. Fatty acid availability in plasma and fatty acid uptake across the splanchnic region and the leg were similar during the basal and clamp experiments. Dextrose infusion decreased fatty acid oxidation by 51.8% (whole body), 47.4% (splanchnic), and 64.3% (leg). Similarly, the percent fatty acid uptake oxidized decreased at the whole body level (53 to 29%), across the splanchnic region (30 to 13%), and in the leg (48 to 22%) during the clamp. We conclude that, in healthy men, combined hyperglycemia-hyperinsulinemia inhibits fatty acid oxidation to a similar extent at the whole body level, across the leg, and across the splanchnic region, even when fatty acid availability is constant.

scholarly journals Allogeneic T Cells up-Regulate Fatty Acid Metabolism and Can Be Targeted Through Metabolic Inhibition of Fatty Acid Oxidation

2013 ◽  
Vol 19 (2) ◽  
pp. S318-S319
Author(s):  
Craig A. Byersdorfer ◽  
Victor Tkachev ◽  
Stefanie Goodell ◽  
Stacy Sandquist ◽  
Anthony W. Opipari ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Metabolic Inhibition ◽  
Acid Oxidation

scholarly journals Zonation of fatty acid metabolism in rat liver

1989 ◽  
Vol 264 (1) ◽  
pp. 107-113 ◽  
Author(s):  
M Guzmán ◽  
J Castro
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Low Density ◽  
Short Term ◽  
Carnitine Palmitoyltransferase I ◽  
Term Response

Fatty acid metabolism was studied in periportal and perivenous hepatocytes isolated by the method of Chen & Katz [Biochem. J. (1988) 255, 99-104]. The rate of fatty acid synthesis and the activity of acetyl-CoA carboxylase were markedly enhanced in perivenous hepatocytes as compared with periportal cells. However, the response of these two parameters to short-term modulation by cellular effectors such as the hormones insulin and glucagon, the phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate and the xenobiotics ethanol and acetaldehyde was similar in the two zones of the liver. In addition, perivenous hepatocytes showed a higher capacity of esterification of exogenous fatty acids into both cellular and very-low-density-lipoprotein lipids. Nevertheless, no difference between the two cell sub-populations seemed to exist in relation to the secretion of very-low-density lipoproteins. On the other hand, the rate of fatty acid oxidation was increased in periportal cells. This could be accounted for by a higher activity of carnitine palmitoyltransferase I and a lower sensitivity of this enzyme to inhibition by malonyl-CoA in the periportal zone. No differences were observed between periportal and perivenous hepatocytes in relation to the short-term response of fatty acid oxidation and carnitine palmitoyltransferase I activity to the cellular modulators mentioned above. In conclusion, our results show that: (i) lipogenesis is achieved at higher rates in the perivenous zone of the liver, whereas the fatty-acid-oxidative process occurs with a certain preference in the periportal area of this organ; (ii) the short-term response of the different fatty-acid-metabolizing pathways to cellular effectors is quantitatively similar in the two zones of the liver.

Control of Fatty Acid Metabolism I. Induction of the Enzymes of Fatty Acid Oxidation in Escherichia coli

1969 ◽  
Vol 97 (2) ◽  
pp. 827-836 ◽  
Author(s):  
Gerald Weeks ◽  
Martin Shapiro ◽  
R. O. Burns ◽  
Salih J. Wakil
Keyword(s):  
Escherichia Coli ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Acid Oxidation

scholarly journals Maternal Feeding of a Synthetic PPARα Agonist Alters Renal Development of Fatty Acid Metabolism in the Neonatal Piglet

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 702-702
Author(s):  
Lin Xi ◽  
Brandon Pike ◽  
Jinan Zhao ◽  
Jack Odle
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Block Design ◽  
Energy Utilization ◽  
Detectable Effect ◽  
Acid Oxidation ◽  
Maternal Supplementation

Abstract Objectives Clofibrate as a therapeutic agent has been used for controlling hyperlipidemias of humans for more than 50 years. Its action, metabolism, half-life and excretion have been well documented in liver of adult humans and rodent species, but it has not been evaluated well in extrahepatic tissues in neonates as a stimulator of energy utilization. In this study, the role of maternal administration of clofibrate in development of renal fatty acid oxidation was evaluated using swine as a model. Methods A randomized complete block design was used with a total of 27 pregnant sows. The sows were fed standard gestation-lactation diets supplemented with either 0 (control), 0.25% or 0.5% clofibrate (w/w) from d 107 of gestation to d 7 of lactation. Fatty acid oxidation was measured in the presence or absence of carnitine (1 mM) or/and malonate (5 mM) in fresh kidney homogenates from piglets at d1, 7, 14 and 19 of age using 14C-oleic acid (1 mM) as substrate (9.9 mBq/mmol). Results Interactions (P < 0.001) were observed between maternal clofibrate levels and postnatal age on 14C accumulation in CO2 (14CO2), acid soluble products (14C-ASP) and esterified products (14C-ESP). The 14CO2 increased by 1.3 fold from d1 to d7, but showed no differences between d7, 14 and 19 in pigs from the control sows. Maternal supplementation of clofibrate increased 14CO2 in pigs across all ages, but the increase was higher in pigs from sows fed 0.5% versus 0.25% clofibrate at d14. The 14C-ASP was 7-fold higher in d1 pigs from control sows than all other ages. Maternal supplementation of clofibrate increased 14C-ASP by 2 fold in pigs at d1, but had no detectable effect at d 7, 14 and 19. The 14C-ESP increased from d1 to d7 and decreased from d7 to d19 in pigs from control sows. Maternal supplementation of clofibrate had no detectable impact on 14C-ESP at d1, 14 and 19, but decreased 14C-ESP measured in d7 pigs. In vitro carnitine supplementation increased 14CO2 and malonate supplementation decreased 14CO2, but neither carnitine nor malonate altered 14C-ASP or 14C-ESP. Conclusions The stimulatory effect of maternal clofibrate on renal fatty acid metabolism in offspring is associated with the postnatal age, being greater at d1 and d7 than d14 and d19. Funding Sources USDA National Institute of Food and Agriculture.

scholarly journals Comparative analysis of sesame lignans (sesamin and sesamolin) in affecting hepatic fatty acid metabolism in rats

2007 ◽  
Vol 97 (1) ◽  
pp. 85-95 ◽  
Author(s):  
Jin Seon Lim ◽  
Yoshikazu Adachi ◽  
Yoko Takahashi ◽  
Takashi Ide
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Liver Lipid ◽  
Mrna Abundance ◽  
Acid Oxidation ◽  
Hepatic Fatty Acid ◽  
Sesame Lignans ◽  
Hepatic Fatty Acid Oxidation

Effects of sesamin and sesamolin (sesame lignans) on hepatic fatty acid metabolism were compared in rats. Rats were fed either a lignan-free diet, a diet containing 0·6 or 2 g/kg lignan (sesamin or sesamolin), or a diet containing both sesamin (1·4 g/kg) and sesamolin (0·6 g/kg), for 10 d. Sesamin and sesamolin dose-dependently increased the activity and mRNA abundance of various enzymes involved in hepatic fatty acid oxidation. The increase was much greater with sesamolin than with sesamin. These lignans increased parameters of hepatic fatty acid oxidation in an additive manner when added simultaneously to an experimental diet. In contrast, they decreased the activity and mRNA abundance of hepatic lipogenic enzymes despite dose-dependent effects not being necessarily obvious. Sesamin and sesamolin were equally effective in lowering parameters of lipogenesis. Sesamolin accumulated in serum at 33- and 46-fold the level of sesamin at dietary concentrations of 0·6 and 2 g/kg, respectively. The amount of sesamolin accumulated in liver was 10- and 7-fold that of sesamin at the respective dietary levels. Sesamolin rather than sesamin can account for the potent physiological effect of sesame seeds in increasing hepatic fatty acid oxidation observed previously. Differences in bio-availability may contribute to the divergent effects of sesamin and sesamolin on hepatic fatty acid oxidation. Sesamin compared to sesamolin was more effective in reducing serum and liver lipid levels despite sesamolin more strongly increasing hepatic fatty acid oxidation.

scholarly journals Species differences in the physiological activity of dietary lignan (sesamin and episesamin) in affecting hepatic fatty acid metabolism

2004 ◽  
Vol 91 (3) ◽  
pp. 377-386 ◽  
Author(s):  
Masayo Kushiro ◽  
Yoko Takahashi ◽  
Takashi Ide
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Animal Species ◽  
Acid Metabolism ◽  
Physiological Activity ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Hepatic Fatty Acid ◽  
Degradation Rates

The effect of sesame (Sesamum orientale) lignan preparation containing equivalent amounts of sesamin and episesamin on hepatic fatty acid metabolism was compared in rats, mice and hamsters. Animals were fed on either a diet free of lignan or a diet containing 2glignan/kg for 15d. The lignan preparation greatly increased hepatic activity and the mRNA levels of enzymes involved in fatty acid oxidation, while it strongly down-regulated those of enzymes involved in lipogenesis in rats. In contrast, lignan did not modify these variables in mice and hamsters. Changes observed, if any, were more attenuated in these mice and hamsters than in rats. Sesamin and episesamin concentrations in serum and liver of animals fed on lignan-containing diets were significantly greater (P<0·05) in rats than in mice and hamsters. Moreover, sesamin:episesamin values in tissues were far from that expected from the value in the lignan preparation given to the animals and were dependent on the animal species. Liver microsomes from each animal species degraded sesamin and episesamin in the presence of NADPH. The combined value of sesamin and episesamin degradation rates was lower in rats than in mice and hamsters. In addition, there was considerable diversity in the specificity of the enzyme reaction toward sesamin and episesamin among animal species. The differences in the amounts of lignan remaining in the tissues may account for the species dependence of the physiological activity of sesame lignan in affecting hepatic fatty acid oxidation and synthesis.

A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and AICAR-stimulated fatty acid metabolism

2007 ◽  
Vol 292 (6) ◽  
pp. E1740-E1749 ◽  
Author(s):  
Arend Bonen ◽  
Xiao-Xia Han ◽  
Daphna D. J. Habets ◽  
Maria Febbraio ◽  
Jan F. C. Glatz ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Critical Role ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Acid Esterification ◽  
White Gastrocnemius ◽  
Fatty Acid Esterification

Fatty acid translocase (FAT)/CD36 is involved in regulating the uptake of long-chain fatty acids into muscle cells. However, the contribution of FAT/CD36 to fatty acid metabolism remains unknown. We examined the role of FAT/CD36 on fatty acid metabolism in perfused muscles (soleus and red and white gastrocnemius) of wild-type (WT) and FAT/CD36 null (KO) mice. In general, in muscles of KO mice, 1) insulin sensitivity and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) sensitivity were normal, 2) key enzymes involved in fatty acid oxidation were altered minimally or not at all, and 3) except for an increase in soleus muscle FATP1 and FATP4, these fatty acid transporters were not altered in red and white gastrocnemius muscles, whereas plasma membrane-bound fatty acid binding protein was not altered in any muscle. In KO muscles perfused under basal conditions (i.e., no insulin, no AICAR), rates of hindquarter fatty acid oxidation were reduced by 26%. Similarly, in oxidative but not glycolytic muscles, the basal rates of triacylglycerol esterification were reduced by 40%. When muscles were perfused with insulin, the net increase in fatty acid esterification was threefold greater in the oxidative muscles of WT mice compared with the oxidative muscles in KO mice. With AICAR-stimulation, the net increase in fatty acid oxidation by hindquarter muscles was 3.7-fold greater in WT compared with KO mice. In conclusion, the present studies demonstrate that FAT/CD36 has a critical role in regulating fatty acid esterification and oxidation, particularly during stimulation with insulin or AICAR.

scholarly journals Maternal Supplementation of Clofibrate Stimulates Hepatic Fatty Acid Oxidation in Newborn Suckling Piglets

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 703-703
Author(s):  
Jinan Zhao ◽  
Brandon Pike ◽  
Jack Odle ◽  
Lin Xi
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Standard Diet ◽  
Hepatic Fatty Acid ◽  
Food And Agriculture ◽  
Hepatic Fatty Acid Oxidation

Abstract Objectives To evaluate effects of maternal feeding of clofibrate, a PPARα agonist, on development of hepatic fatty acid metabolism in offspring using pig as a model. Methods Pregnant sows (N = 27) were randomly assigned into three treatment groups. Each group was fed a standard diet (3265 kcal ME/kg) supplemented with either 0, 0.25% or 5% clofibrate (w/w) from d 107 of gestation to d 7 of lactation. Liver tissue was collected from piglets at birth, d1, 7, 14 and 19. Fatty acid oxidation was examined in fresh homogenates using 1 mM [1–14C] oleic acid (9.9 mBq/mmol) as substrate. Oxidation was measured in the absence or presence of in vitro supplemented L-carnitine (1 mM) and/or malonate (5 mM). Results Clofibrate was not detected in piglet liver or sow milk. Interactions between clofibrate and postnatal age (P &lt; 0.001) on the 14C accumulation in 14CO2, acid soluble products (14C-ASP) and esterified products (14C-ESP) were observed. Accumulation in 14CO2 was not altered by piglet age in control sows; however, accumulation in 14C-ASP was higher at d14 and lower at d19 compared to d1. In contrast, maternal clofibrate increased 14CO2 by 100% and 14C-ASP by 80% in pigs at d1, and the increase was higher in pigs from sows given 0.5% versus 0.25% clofibrate. Accumulation in 14C-ESP in pigs from control sows increased from d1 to d14, but there was no difference detected between d14 and 19. Assessment of pigs from sows fed the 0.25% clofibrate dose revealed no impact on 14C-ESP, but the 0.5% dose increased 14C-ESP by 31%. No interaction was observed between clofibrate and the in vitro treatments (carnitine and malonate; P = 0.5). In vitro supplementation of carnitine increased radiolabel accumulation in CO2 by 60% and in ASP by 120%, but reduced 14C-ESP by 39% compared to control incubations. Supplementation of malonate reduced 14CO2 by 95% and 14C-ESP by 44%, but had no impact on 14C-ASP. Conclusions Maternal clofibrate enhances hepatic fatty acid metabolism in offspring, but the effect fades with postpartum age. The availability of carnitine in the milk could be a key element to support fatty acid oxidation in postnatal pigs. Funding Sources USDA National Institute of Food and Agriculture.

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