scholarly journals c-MYC Triggers Lipid Remodelling During Early Somatic Cell Reprogramming to Pluripotency

2021 ◽  
Author(s):  
Javier Prieto ◽  
Juan Carlos García-Cañaveras ◽  
Marian León ◽  
Ramón Sendra ◽  
Xavier Ponsoda ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Proliferation ◽  
Fatty Acid ◽  
Somatic Cell ◽  
Pentose Phosphate Pathway ◽  
Aerobic Glycolysis ◽  
Pentose Phosphate ◽  
High Rate ◽  
Cell Reprogramming ◽  
Acyl Chains

AbstractMetabolic rewiring and mitochondrial dynamics remodelling are hallmarks of cell reprogramming, but the roles of the reprogramming factors in these changes are not fully understood. Here we show that c-MYC induces biosynthesis of fatty acids and increases the rate of pentose phosphate pathway. Time-course profiling of fatty acids and complex lipids during cell reprogramming using lipidomics revealed a profound remodelling of the lipid content, as well as the saturation and length of their acyl chains, in a c-MYC-dependent manner. Pluripotent cells displayed abundant cardiolipins and scarce phosphatidylcholines, with a prevalence of monounsaturated acyl chains. Cells undergoing cell reprogramming showed an increase in mitochondrial membrane potential that paralleled that of mitochondrial-specific cardiolipins. We conclude that c-MYC controls the rewiring of somatic cell metabolism early in cell reprogramming by orchestrating cell proliferation, synthesis of macromolecular components and lipid remodelling, all necessary processes for a successful phenotypic transition to pluripotency. Graphical Abstract c-MYC promotes anabolic metabolism, mitochondrial fitness and lipid remodelling early in cell reprogramming. A high rate of aerobic glycolysis is crucial to provide intermediaries for biosynthetic pathways. To ensure the availability of nucleotides, amino acids and lipids for cell proliferation, cells must provide with a constant flux of the elemental building blocks for macromolecule assembly and fulfil the anabolic demands to reach the critical cellular mass levels to satisfactorily undergo cell division. A high rate of aerobic glycolysis is induced by c-MYC, increasing the amounts of intracellular Glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), and glyceraldehyde-3-phosphate (GA3P), which can all enter pentose phosphate pathway (PPP) to produce Ribose-5-Phosphate (R5P) and NADPH, which are necessary for the biosynthesis of biomolecules such as proteins, nucleic acids, or lipids. C-MYC-dependent activation of glucose-6-phosphate dehydrogenase (G6PD) may play a critical role in the shunting of G6P to PPP and generation of NADPH. High glycolytic flux increases the amounts of dihydroxyacetone phosphate (DHAP), which is crucial for biosynthesis of phospholipids and triacylglycerols, and pyruvate (Pyr), which can be converted to citrate (Cit) in the mitochondria and enter the biosynthesis of fatty acids (FA). During cell reprogramming, c-MYC-dependent lipid remodelling leads to Polyunsaturated Fatty Acid (PUFA) downregulation and Monounsaturated Fatty Acid (MUFA) upregulation, which may play critical roles in cytoarchitectural remodelling of cell membrane or non-canonical autophagy, respectively. Cardiolipin (pink dots) rise early in cell reprogramming correlates with an increase in mitochondrial fitness, suggesting that c-MYC may restore proper levels of cardiolipins and antioxidant proteins, such as UCP2, to guarantee an optimal mitochondrial function while upholding ROS levels, reinforcing the idea of cell rejuvenation early in cell reprogramming.

scholarly journals Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation

Oncotarget ◽  
2015 ◽  
Vol 7 (3) ◽  
pp. 2910-2920 ◽  
Author(s):  
Géraldine De Preter ◽  
Marie-Aline Neveu ◽  
Pierre Danhier ◽  
Lucie Brisson ◽  
Valéry L. Payen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Pentose Phosphate Pathway ◽  
Aerobic Glycolysis ◽  
Pentose Phosphate ◽  
Cancer Cell Proliferation ◽  
Missing Link

Contribution of pentose phosphate pathway in developing castor bean endosperm

1971 ◽  
Vol 49 (2) ◽  
pp. 267-272 ◽  
Author(s):  
P. K. Agrawal ◽  
D. T. Canvin
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Pentose Phosphate Pathway ◽  
Castor Bean ◽  
Lipid Synthesis ◽  
Experimental Period ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
Fat Synthesis

Glucose-1-14C, glucose-6-14C, and glucose-U-14C were used to calculate the contribution of the PPP in developing castor bean endosperm tissues. Depending on the age of the seed 5–12% of the glucose-14C used was metabolized via the PPP and 88–95% via the EMP pathway. When lipid synthesis was rapid (20- to 28-day period) the PPP contribution was also at a maximum. During the 30- to 51-day period when lipid synthesis decreased so did the PPP contribution.With the data obtained from the PPP contribution the amount of NADPH produced during the experimental period was calculated. Also, the amount of fatty acids synthesized during that period was determined from glucose-U-14C data and thus the amount of NADPH required was calculated. Assuming that all the NADPH produced in the PPP was utilizable in fatty acid synthesis it was found that it was only sufficient to supply 50–75% of the reducing hydrogen required for fat synthesis. Therefore, the rest of the reducing hydrogen must come from some other sources, possibly NADH.

scholarly journals Free Fatty acids receptors (FFAR2 and FFAR3) control cell proliferation by regulating cellular glucose uptake

2019 ◽  
Author(s):  
Mohammad Aziz ◽  
Saeed Al Mahri ◽  
Amal Alghamdi ◽  
Maaged AlAkiel ◽  
Monira Al Aujan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fatty Acids ◽  
Cell Proliferation ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Glucose Uptake ◽  
Microarray Data ◽  
Free Fatty Acid Receptors

Abstract Background Colorectal cancer is a worldwide problem which has been associated with changes in diet and lifestyle pattern. As a result of colonic fermentation of dietary fibres, short chain free fatty acids are generated which activate Free Fatty Acid Receptors 2 and 3 (FFAR2 and FFAR3). FFAR2 and FFAR3 genes are abundantly expressed in colonic epithelium and play an important role in the metabolic homeostasis of colonic epithelial cells. Earlier studies point to the involvement of FFAR2 in colorectal carcinogenesis. Methods Transcriptome analysis console was used to analyse microarray data from patients and cell lines. We employed shRNA mediated down regulation of FFAR2 and FFAR3 genes which was assessed using qRT-PCR. Assays for glucose uptake and cAMP generation was done along with immunofluorescence studies. For measuring cell proliferation, we employed real time electrical impedance based assay available from xCelligence. Results Microarray data analysis of colorectal cancer patient samples showed a significant down regulation of FFAR2 gene expression. This prompted us to study the FFAR2 in colorectal cancer. Since, FFAR3 shares significant structural and functional homology with FFAR2, we knocked down both these receptors in colorectal cancer cell line HCT 116. These modified cell lines exhibited higher proliferation rate and were found to have increased glucose uptake as well as increased level of GLUT1. Since, FFAR2 and FFAR3 signal through G protein subunit (Gαi), knockdown of these receptors was associated with increased cAMP. Inhibition of PKA did not alter the growth and proliferation of these cells indicating a mechanism independent of cAMP/PKA pathway. Conclusion: Our results suggest role of FFAR2/FFAR3 genes in increased proliferation of colon cancer cells via enhanced glucose uptake and exclude the role of protein kinase A mediated cAMP signalling. Alternate pathways could be involved that would ultimately result in increased cell proliferation as a result of down regulated FFAR2/FFAR3 genes. This study paves the way to understand the mechanism of action of short chain free fatty acid receptors in colorectal cancer.

scholarly journals Peroxisome-proliferator-activated receptor δ mediates the effects of long-chain fatty acids on post-confluent cell proliferation

2000 ◽  
Vol 350 (1) ◽  
pp. 93-98 ◽  
Author(s):  
Chantal JEHL-PIETRI ◽  
Claire BASTIE ◽  
Isabelle GILLOT ◽  
Serge LUQUET ◽  
Paul A. GRIMALDI
Keyword(s):  
Fatty Acids ◽  
Cell Proliferation ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Long Chain Fatty Acids ◽  
Control Of Gene Expression ◽  
Long Chain ◽  
Chain Fatty Acids

Nutritional long-chain fatty acids control adipose tissue mass by regulating the number and the size of adipocytes. It is now established that peroxisome-proliferator-activated receptors (PPARs) play crucial functions in the control of gene expression and the level of cell differentiation. PPARγ, which is activated by specific prostanoids, is a key factor in activating terminal differentiation and adipogenesis. We have recently demonstrated that PPARδ, once activated by fatty acids, drives the expression of a limited set of genes, including that encoding PPARγ, thereby inducing adipose differentiation. Thus far, the mechanism of action of fatty acids in the control of preadipocyte proliferation has remained unknown. We show here that PPARδ is directly implicated in fatty acid-induced cell proliferation. Ectopic expression of PPARδ renders 3T3C2 cells capable of responding to treatment with long-chain fatty acids by a resumption of mitosis, and this effect is limited to a few days after confluence. This response is restricted to PPARδ activators and, for fatty acids, takes place within the range of concentrations found to trigger differentiation of preadipocytes both in vitro and in vivo. Furthermore, the use of a mutated inactive PPARδ demonstrated that transcriptional activity of the nuclear receptor is required to mediate fatty acid-induced proliferation. These data demonstrate that PPARδ, as a transcription factor, is directly implicated in fatty acid-induced proliferation, and this could explain the hyperplastic development of adipose tissue that occurs in high-fat-fed animals.

scholarly journals Circadian Feeding Drive of Metabolic Activity in Adipose Tissue and not Hyperphagia Triggers Overweight in Mice: Is There a Role of the Pentose-Phosphate Pathway?

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 690-699 ◽  
Author(s):  
Paula Stucchi ◽  
Marta Gil-Ortega ◽  
Beatriz Merino ◽  
Rocío Guzmán-Ruiz ◽  
Victoria Cano ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Food Intake ◽  
Pentose Phosphate Pathway ◽  
Fatty Acid Synthase ◽  
Pentose Phosphate ◽  
Plasma Parameters ◽  
Dependent Protein Kinase ◽  
Dependent Protein

High-fat (HF) diets trigger an increase in adipose tissue and body weight (BW) and disordered eating behavior. Our study deals with the hypothesis that circadian distribution of energy intake is more relevant for BW dynamics than diet composition. Four-week-old mice were exposed for 8 wk to a HF diet and compared with animals receiving control chow. HF mice progressively increased BW, decreased the amount of nocturnal (1800–0900 h) calories (energy or food intake) (30%) and increased diurnal (0900–1800 h) caloric intake (energy or food intake), although total daily intake was identical between groups. Animals were killed at 3-h intervals and plasma insulin, leptin, corticosterone, glucose, and fatty acid levels quantified. Adipose tissue was weighed, and enzymatic activities integral to the pentose phosphate pathway (PPP) assayed in lumbar adipose tissue. Phosphorylated AMP-dependent protein kinase and fatty acid synthase were quantified by Western blotting. In HF mice, there was a shift in the circadian oscillations of plasma parameters together with an inhibition of PPP activity and a decrease in phosphorylated AMP-dependent protein kinase and fatty acid synthase. In a second experiment, HF mice were forced to adhere to a circadian pattern of food intake similar to that in control animals. In this case, BW, adipose tissue, morning plasma parameters and PPP activity appeared to be normal. These data indicate that disordered feeding behavior can trigger BW gain independently of food composition and daily energy intake. Because PPP is the main source of reduced nicotinamide adenine dinucleotide phosphate, we suggest that PPP inhibition might be an early marker of adipose dysfunction in diet-induced obesity.

scholarly journals Lipidomics reveal the protective effects of a vegetable-derived isothiocyanate against retinal degeneration

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1067 ◽  
Author(s):  
Faith A. Kwa ◽  
Nabeela K. Dulull ◽  
Ute Roessner ◽  
Daniel A. Dias ◽  
Thusitha W. Rupasinghe
Keyword(s):  
Oxidative Stress ◽  
Mass Spectrometry ◽  
Hydrogen Peroxide ◽  
Fatty Acids ◽  
Cell Proliferation ◽  
Fatty Acid ◽  
Oxidative Damage ◽  
Disease Progression ◽  
Protective Effects ◽  
Retinal Cells

Background: Age-related macular degeneration (AMD) is a leading cause of blindness in the ageing population. Without effective treatment strategies that can prevent disease progression, there is an urgent need for novel therapeutic interventions to reduce the burden of vision loss and improve patients’ quality of life. Dysfunctional innate immune responses to oxidative stress observed in AMD can be caused by the formation of oxidised lipids, whilst polyunsaturated fatty acids have shown to increase the risk of AMD and disease progression in affected individuals. Previously, our laboratory has shown that the vegetable-derived isothiocyanate, L-sulforaphane (LSF), can protect human adult pigment epithelial cells from oxidative damage by upregulating gene expression of the oxidative stress enzyme Glutathione-S-Transferase µ1. This study aims to validate the protective effects of LSF on human retinal cells under oxidative stress conditions and to reveal the key players in fatty acid and lipid metabolism that may facilitate this protection. Methods: The in vitro oxidative stress model of AMD was based on the exposure of an adult retinal pigment epithelium-19 cell line to 200µM hydrogen peroxide. Percentage cell proliferation following LSF treatment was measured using tetrazolium salt-based assays. Untargeted fatty acid profiling was performed by gas chromatography-mass spectrometry. Untargeted lipid profiling was performed by liquid chromatography-mass spectrometry. Results: Under hydrogen peroxide-induced oxidative stress conditions, LSF treatment induced dose-dependent cell proliferation. The key fatty acids that were increased by LSF treatment of the retinal cells include oleic acid and eicosatrienoic acid. LSF treatment also increased levels of the lipid classes phosphatidylcholine, cholesteryl ester and oxo-phytodienoic acid but decreased levels of phosphatidylethanolamine lipids. Conclusions: We propose that retinal cells at risk of oxidative damage and apoptosis can be pre-conditioned with LSF to regulate levels of selected fatty acids and lipids known to be implicated in the pathogenesis and progression of AMD.

scholarly journals TAp73 enhances the pentose phosphate pathway and supports cell proliferation

2013 ◽  
Vol 15 (8) ◽  
pp. 991-1000 ◽  
Author(s):  
Wenjing Du ◽  
Peng Jiang ◽  
Anthony Mancuso ◽  
Aaron Stonestrom ◽  
Michael D. Brewer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pentose Phosphate Pathway ◽  
Pentose Phosphate

scholarly journals The elongation of exogenous fatty acids and the control of phospholipid acyl chain length in Micrococcus cryophilus

1980 ◽  
Vol 188 (3) ◽  
pp. 585-592 ◽  
Author(s):  
S P Sandercock ◽  
N J Russell
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Chain Length ◽  
De Novo ◽  
Acyl Chain ◽  
Psychrophilic Bacterium ◽  
Fatty Acid Elongation ◽  
Acyl Chain Length ◽  
Acyl Chains ◽  
Phospholipid Acyl Chain

The synthesis of fatty acids de novo from acetate and the elongation of exogenous satuated fatty acids (C12-C18) by the psychrophilic bacterium Micrococcus cryophilus (A.T.C.C. 15174) grown at 1 or 20 degrees C was investigated. M. cryophilus normally contains only C16 and C18 acyl chains in its phospholipids, and the C18/C16 ratio is altered by changes in growth temperature. The bacterium was shown to regulate strictly its phospholipid acyl chain length and to be capable of directly elongating myristate and palmitate, and possibly laurate, to a mixture of C16 and C18 acyl chains. Retroconversion of stearate into palmitate also occurred. Fatty acid elongation could be distinguished from fatty acid synthesis de novo by the greater sensitivity of fatty acid elongation to inhibition by NaAsO2 under conditions when the supply of ATP and reduced nicotinamide nucleotides was not limiting. It is suggested that phospholipid acyl chain length may be controlled by a membrane-bound elongase enzyme, which interconverts C16 and C18 fatty acids via a C14 intermediate; the activity of the enzyme could be regulated by membrane lipid fluidity.

Sign in / Sign up

Export Citation Format

Share Document