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

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.

Download Full-text

LIF and CNTF, which share the gp130 transduction system, stimulate hepatic lipid metabolism in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.3.e521 ◽

1996 ◽

Vol 271 (3) ◽

pp. E521-E528 ◽

Cited By ~ 4

Author(s):

K. Nonogaki ◽

X. M. Pan ◽

A. H. Moser ◽

J. Shigenaga ◽

I. Staprans ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Synthesis ◽

De Novo ◽

Acid Synthesis ◽

Interleukin 4 ◽

Dependent Manner ◽

Hepatic Triglyceride ◽

Serum Triglycerides ◽

Triglyceride Secretion

We determined the effects of leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) on lipid metabolism in intact rats. Administration of LIF and CNTF increased serum triglycerides in a dose-dependent manner with peak values at 2 h. The effects of LIF and CNTF on serum cholesterol were very small, and serum glucose was unaffected. Both LIF and CNTF stimulated hepatic triglyceride secretion, hepatic de novo fatty acid synthesis, and lipolysis. Pretreatment with phenylisopropyl adenosine, which inhibits lipolysis, partially inhibited LIF- and CNTF-induced hypertriglyceridemia. Interleukin-4, which inhibits cytokine-induced hepatic fatty acid synthesis, also partially inhibited LIF- and CNTF-induced hypertriglyceridemia. These results indicate that both lipolysis and de novo fatty acid synthesis play a role in providing fatty acids for the increase in hepatic triglyceride secretion. Neither indomethacin nor adrenergic receptor antagonists affected the hypertriglyceridemia. The combination of LIF plus CNTF showed no additive effects consistent with the action of both cytokines through the gp130 transduction system. Thus LIF and CNTF have similar effects on lipid metabolism; they join a growing list of cytokines that stimulate hepatic triglyceride secretion and may mediate the changes in lipid metabolism that accompany the acute phase response.

Download Full-text

Taurine-Mediated IDOL Contributes to Resolution of Streptococcus uberis Infection

Infection and Immunity ◽

10.1128/iai.00788-20 ◽

2021 ◽

Vol 89 (5) ◽

Author(s):

Zhixin Wan ◽

Riguo Lan ◽

Yilin Zhou ◽

Yuanyuan Xu ◽

Zhenglei Wang ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Synthesis ◽

De Novo ◽

Bacterial Load ◽

Critical Role ◽

Acid Synthesis ◽

Content Type ◽

Streptococcus Uberis

ABSTRACT Metabolic alterations occur in pathogenic infections, but the role of lipid metabolism in the progression of bacterial mastitis is unclear. Cross talk between lipid droplets (LDs) and invading bacteria occurs, and targeting of de novo lipogenesis inhibits pathogen reproduction. In this study, we investigate the role(s) of lipid metabolism in mammary cells during Streptococcus uberis infection. Our results indicate that S. uberis induces the synthesis of fatty acids and production of LDs. Importantly, taurine reduces fatty acid synthesis, the abundance of LDs and the in vitro bacterial load of S. uberis. These changes are mediated, at least partly, by the E3 ubiquitin ligase IDOL, which is associated with the degradation of low-density lipoprotein receptors (LDLRs). We have identified a critical role for IDOL-mediated fatty acid synthesis in bacterial infection, and we suggest that taurine may be an effective prophylactic or therapeutic strategy for preventing S. uberis mastitis.

Download Full-text

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

Cells ◽

10.3390/cells9122600 ◽

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.

Download Full-text

Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism

Nature Metabolism ◽

10.1038/s42255-020-0211-z ◽

2020 ◽

Vol 2 (6) ◽

pp. 499-513 ◽

Cited By ~ 2

Author(s):

Michael Aregger ◽

Keith A. Lawson ◽

Maximillian Billmann ◽

Michael Costanzo ◽

Amy H. Y. Tong ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Synthesis ◽

De Novo ◽

Acid Synthesis ◽

Genetic Interactions ◽

Systematic Mapping

Download Full-text

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

Cancers ◽

10.3390/cancers12113152 ◽

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.

Download Full-text

Conjugated Linoleic Acid (t-10, c-12) Reduces Fatty Acid Synthesis de Novo, but not Expression of Genes for Lipid Metabolism in Bovine Adipose Tissue ex Vivo

Lipids ◽

10.1007/s11745-013-3869-0 ◽

2013 ◽

Vol 49 (1) ◽

pp. 15-24 ◽

Cited By ~ 14

Author(s):

Seong Ho Choi ◽

David T. Silvey ◽

Bradley J. Johnson ◽

Matthew E. Doumit ◽

Ki Yong Chung ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Linoleic Acid ◽

Conjugated Linoleic Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Ex Vivo ◽

Acid Synthesis ◽

Expression Of Genes

Download Full-text

The Lipid Metabolic Landscape of Cancers and New Therapeutic Perspectives

Frontiers in Oncology ◽

10.3389/fonc.2020.605154 ◽

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.

Download Full-text

Synthesis of fatty acids in the perfused mouse liver

Biochemical Journal ◽

10.1042/bj1420611 ◽

1974 ◽

Vol 142 (3) ◽

pp. 611-618 ◽

Cited By ~ 57

Author(s):

D. Michael W. Salmon ◽

Neil L. Bowen ◽

Douglas A. Hems

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Saturated Fatty Acids ◽

Carbon Sources ◽

Acid Synthesis ◽

Hepatic Glycogen ◽

Total Rate ◽

Glucose Carbon

1. Fatty acid synthesis de novo was measured in the perfused liver of fed mice. 2. The total rate, measured by the incorporation into fatty acid of3H from3H2O (1–7μmol of fatty acid/h per g of fresh liver), resembled the rate found in the liver of intact mice. 3. Perfusions with l-[U-14C]lactic acid and [U-14C]glucose showed that circulating glucose at concentrations less than about 17mm was not a major carbon source for newly synthesized fatty acid, whereas lactate (10mm) markedly stimulated fatty acid synthesis, and contributed extensive carbon to lipogenesis. 4. The identification of 50% of the carbon converted into newly synthesized fatty acid lends further credibility to the use of3H2O to measure hepatic fatty acid synthesis. 5. The total rate of fatty acid synthesis, and the contribution of glucose carbon to lipogenesis, were directly proportional to the initial hepatic glycogen concentration. 6. The proportion of total newly synthesized lipid that was released into the perfusion medium was 12–16%. 7. The major products of lipogenesis were saturated fatty acids in triglyceride and phospholipid. 8. The rate of cholesterol synthesis, also measured with3H2O, expressed as acetyl residues consumed, was about one-fourth of the basal rate of fatty acid synthesis. 9. These results are discussed in terms of the carbon sources of hepatic newly synthesized fatty acids, and the effect of glucose, glycogen and lactate in stimulating lipogenesis, independently of their role as precursors.

Download Full-text

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00032.2013 ◽

2013 ◽

Vol 305 (2) ◽

pp. E205-E212 ◽

Cited By ~ 45

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.

Download Full-text