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 De Novo Fatty Acid Synthesis-Driven Sphingolipid Metabolism Promotes Metastatic Potential of Colorectal Cancer

2018 ◽  
Vol 17 (1) ◽  
pp. 140-152 ◽  
Author(s):  
Naser Jafari ◽  
James Drury ◽  
Andrew J. Morris ◽  
Fredrick O. Onono ◽  
Payton D. Stevens ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Metastatic Potential ◽  
Acid Synthesis ◽  
Sphingolipid Metabolism

scholarly journals Analysis of lines of mice selected for fat content: 3. Flux through the de novo lipid synthesis pathway

1991 ◽  
Vol 58 (2) ◽  
pp. 123-127 ◽  
Author(s):  
Emmanuel A. Asante ◽  
William G. Hill ◽  
Grahame Bulfield
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Lipid Synthesis ◽  
Fold Increase ◽  
Acid Synthesis ◽  
Fat Content ◽  
Direct Selection ◽  
Lean Line

SummaryThe flux through the de novo fatty acid synthesis pathway was estimated in lines of mice which differed substantially in fat content following 26 generations of selection at 10 weeks of age. Previous estimates of lipogenic enzyme activities had indicated an increase in the capacity for lipogenesis in the Fat compared to the Lean line. Therefore the in vivo flux in lipogenesis was measured in both liver and gonadal fat pad (GFP) tissues of males at 5 and 10 weeks of age, using the rat of incorporation of 3H from 3H2O and 14C from acetate and citra te into total lipids. AT both ages and in both tissues the Fat line had a higher flux, about 20% increase in the liver and up to three-fold increase (range 1·2- to 3·4-fold) in the GFP. We conclude that direct selection for fatness in mice has resulted in metabolic changes in the ratio of de novo fatty acid synthesis, and that the changes are largely detectable before 10 weeks, the age of selection.

Redefining the role of de novo fatty acid synthesis in Plasmodium parasites

2009 ◽  
Vol 25 (12) ◽  
pp. 545-550 ◽  
Author(s):  
Alice S. Tarun ◽  
Ashley M. Vaughan ◽  
Stefan H.I. Kappe
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Acid Synthesis

Development of lipogenesis and insulin sensitivity in tissues of the ob/ob mouse

1981 ◽  
Vol 240 (2) ◽  
pp. E101-E107 ◽  
Author(s):  
M. L. Kaplan ◽  
G. A. Leveille
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Glycogen Synthesis ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Glycerophosphate Dehydrogenase

Lipogenesis and insulin sensitivity are evaluated in adipose tissue, liver, and diaphragm of ob/ob and non-ob/ob mice. In ob/ob mice, hepatic fatty acid synthesis from [U-14C]glucose is elevated by 4 wk of age, and adipose tissue fatty acid synthesis increases at approximately 7 wk. Hepatic activities in ob/ob mice of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), 6-phosphogluconate dehydrogenase (EC 1.1.1.44), malate dehydrogenase (EC 1.1.1.40), and alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) are dramatically increased by 7 wk of age. Diminished insulin-stimulated glycogen synthesis is first noted in the diaphragm of ob/ob mice at 7 wk of age. Insulin-stimulated glycogen synthesis in adipose tissue of ob/ob mice is impaired at 3 wk. At 7 wk, insulin-stimulated fatty acid synthesis in adipose tissue of ob/ob mice is markedly increased. Adipose tissue glyceride-glycerol synthesis continues to increase throughout development, whereas fatty acid synthesis decreases after 7 wk. The data suggest that alterations in lipid synthesis occur very early in the development of ob/ob mouse, prior to expression to overt obesity, at which time a major contribution to lipogenesis is made by the liver. The altered de novo lipogenesis does not precede the reported diminution in energy metabolism.

scholarly journals Fatty Acid Synthesis and Degradation Interplay to Regulate the Oxidative Stress in Cancer Cells

2019 ◽  
Vol 20 (6) ◽  
pp. 1348 ◽  
Author(s):  
Valeryia Mikalayeva ◽  
Ieva Ceslevičienė ◽  
Ieva Sarapinienė ◽  
Vaidotas Žvikas ◽  
Vytenis Skeberdis ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cancer Cells ◽  
Fatty Acid Synthesis ◽  
Breast Cancer Cells ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Synthesis And Degradation

Both cytosolic fatty acid synthesis (FAS) and mitochondrial fatty acid oxidation (FAO) have been shown to play a role in the survival and proliferation of cancer cells. This study aimed to confirm experimentally whether FAS and FAO coexist in breast cancer cells (BCC). By feeding cells with 13C-labeled glutamine and measuring labeling patterns of TCA intermediates, it was possible to show that part of the cytosolic acetyl-CoA used in lipid synthesis is also fed back into the mitochondrion via fatty acid degradation. This results in the transfer of reductive potential from the cytosol (in the form of NADPH) to the mitochondrion (in the form of NADH and FADH2). The hypothesized mechanism was further confirmed by blocking FAS and FAO with siRNAs. Exposure to staurosporine (which induces ROS production) resulted in the disruption of simultaneous FAS and FAO, which could be explained by NADPH depletion.

scholarly journals Delayed Feeding Alters Transcriptional and Post-Transcriptional Regulation of Hepatic Metabolic Pathways in Peri-Hatch Broiler Chicks

Genes ◽  
2019 ◽  
Vol 10 (4) ◽  
pp. 272 ◽  
Author(s):  
Julie A. Hicks ◽  
Tom E. Porter ◽  
Nishanth E. Sunny ◽  
Hsiao-Ching Liu
Keyword(s):  
Oxidative Stress ◽  
Energy Source ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Metabolic Pathways ◽  
Acid Synthesis ◽  
Feed Consumption ◽  
Acid Oxidation ◽  
Metabolic Switch ◽  
Hepatic Expression

Hepatic fatty acid oxidation of yolk lipoproteins provides the main energy source for chick embryos. Post-hatching these yolk lipids are rapidly exhausted and metabolism switches to a carbohydrate-based energy source. We recently demonstrated that many microRNAs (miRNAs) are key regulators of hepatic metabolic pathways during this metabolic switching. MiRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression in most eukaryotes. To further elucidate the roles of miRNAs in the metabolic switch, we used delayed feeding for 48 h to impede the hepatic metabolic switch. We found that hepatic expression of several miRNAs including miR-33, miR-20b, miR-34a, and miR-454 was affected by delaying feed consumption for 48 h. For example, we found that delayed feeding resulted in increased miR-20b expression and conversely reduced expression of its target FADS1, an enzyme involved in fatty acid synthesis. Interestingly, the expression of a previously identified miR-20b regulator FOXO3 was also higher in delayed fed chicks. FOXO3 also functions in protection of cells from oxidative stress. Delayed fed chicks also had much higher levels of plasma ketone bodies than their normal fed counterparts. This suggests that delayed fed chicks rely almost exclusively on lipid oxidation for energy production and are likely under higher oxidative stress. Thus, it is possible that FOXO3 may function to both limit lipogenesis as well as to help protect against oxidative stress in peri-hatch chicks until the initiation of feed consumption. This is further supported by evidence that the FOXO3-regulated histone deacetylase (HDAC2) was found to recognize the FASN (involved in fatty acid synthesis) chicken promoter in a yeast one-hybrid assay. Expression of FASN mRNA was lower in delayed fed chicks until feed consumption. The present study demonstrated that many transcriptional and post-transcriptional mechanisms, including miRNA, form a complex interconnected regulatory network that is involved in controlling lipid and glucose molecular pathways during the metabolic transition in peri-hatch chicks.

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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