scholarly journals Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression

EBioMedicine ◽  
2015 ◽  
Vol 2 (8) ◽  
pp. 808-824 ◽  
Author(s):  
Richard Ventura ◽  
Kasia Mordec ◽  
Joanna Waszczuk ◽  
Zhaoti Wang ◽  
Julie Lai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Cell Membranes ◽  
Fatty Acid Synthase ◽  
De Novo

scholarly journals Gene expressions of de novo hepatic lipogenesis in feline hepatic lipidosis

2019 ◽  
Vol 22 (6) ◽  
pp. 500-505
Author(s):  
Chiara Valtolina ◽  
Joris H Robben ◽  
Monique E van Wolferen ◽  
Hedwig S Kruitwagen ◽  
Ronald J Corbee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Liver Tissue ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Hepatic Lipidosis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Objectives The aim of this study was to evaluate if de novo hepatic lipid synthesis contributes to fatty acid overload in the liver of cats with feline hepatic lipidosis (FHL). Methods Lipogenic gene expression of peroxisome proliferator-activated receptor-alpha ( PPAR-α), peroxisome proliferator-activated receptor-gamma ( PPAR-γ), fatty acid synthase ( FASN) and sterol regulatory element-binding factor ( SREBF1) were evaluated using quantitative RT-PCR in liver tissue of six cats with FHL and compared with the liver tissue of eight healthy cats. Results In liver tissue, PPAR-α, PPAR-γ and FASN mRNA expression levels were not significantly different ( P >0.12, P >0.89 and P >0.5, respectively) in the FHL group compared with the control group. SREBF1 gene expression was downregulated around 10-fold in the FHL group vs the control group ( P = 0.039). Conclusions and relevance The downregulation of SREBF1 in the liver tissue of cats with FHL does not support the hypothesis that de novo lipogenesis in the liver is an important pathway of fatty acid accumulation in FHL.

scholarly journals Complex Alterations of Fatty Acid Metabolism and Phospholipidome Uncovered in Isolated Colon Cancer Epithelial Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 6650
Author(s):  
Jiřina Hofmanová ◽  
Josef Slavík ◽  
Miroslav Ciganek ◽  
Petra Ovesná ◽  
Zuzana Tylichová ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Fatty Acid ◽  
Epithelial Cells ◽  
Tumor Cells ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Fatty Acid Desaturase ◽  
Fatty Acid Elongase ◽  
Altered Expression ◽  
Long Chain

The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM+ cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer.

scholarly journals Hormonal regulation and cellular localization of fatty acid synthase in human fetal lung

1999 ◽  
Vol 277 (2) ◽  
pp. L381-L390 ◽  
Author(s):  
Sameer Wagle ◽  
Anh Bui ◽  
Philip L. Ballard ◽  
Henry Shuman ◽  
John Gonzales ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Epithelial Cells ◽  
Hormonal Regulation ◽  
Cellular Localization ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Fetal Lung ◽  
Type Ii ◽  
Fas Mrna

Fatty acid synthase (FAS; EC 2.3.1.85 ) supplies de novo fatty acids for pulmonary surfactant synthesis, and FAS gene expression is both developmentally and hormonally regulated in the fetal lung. To further examine hormonal regulation of FAS mRNA and to determine the cellular localization of FAS gene expression, we cultured human fetal lungs (18–22 wk gestation) as explants for 1–4 days in the absence (control) or presence of glucocorticoid [dexamethasone (Dex), 10 nM] and/or cAMP agents (8-bromo-cAMP, 0.1 mM and IBMX, 0.1 mM). FAS protein content and activity increased similarly in the presence of Dex (109 and 83%, respectively) or cAMP (87 and 111%, respectively), and responses were additive in the presence of both hormones (230 and 203%, respectively). With a rabbit anti-rat FAS antibody, FAS immunoreactivity was not detected in preculture lung specimens but appeared in epithelial cells lining the tubules with time in culture. Dex and/or cAMP markedly increased staining of epithelial cells, identified as type II cells, whereas staining of mesenchymal fibroblasts was very low under all conditions. With in situ hybridization, FAS mRNA was found to be enriched in epithelial cells lining the alveolar spaces, and the reaction product increased in these cells when the explants were cultured with the hormones. The increased FAS mRNA content in the presence of Dex and/or cAMP is primarily due to increased stabilization of mRNA, although Dex alone increased the transcription rate by ∼30%. We conclude that hormonal treatment of cultured human fetal lungs increases FAS gene expression primarily by increasing stability of the message. The induction of FAS during explant culture and by hormones occurs selectively in type II epithelial cells, consistent with the regulatory role of this enzyme in de novo synthesis of fatty acid substrate for surfactant synthesis in perinatal lungs.

scholarly journals Beet (Beta vulgaris) Suppressed Gene Expression and Serum Fatty Acid Synthase in High Fat and Fructose-induced Rats

2021 ◽  
Vol 9 (A) ◽  
pp. 303-307
Author(s):  
Salma Nadiyah ◽  
Pramudji Hastuti ◽  
Sunarti Sunarti
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Quantitative Polymerase Chain Reaction ◽  
Colorimetric Method ◽  
Bioactive Compound ◽  
Standard Diet ◽  
High Fat ◽  
Serum Fatty Acid

BACKGROUND: The expression and activity of fatty acid synthase (FAS) enzymes determine de novo fatty acid synthesis, which can be enhanced by a high-fat and high fructose diet or inhibited by some bioactive compound diets. Beets are a great source of therapeutic compounds that have the potential to improve health and prevent disease. AIM: This study examined the effects of beets on liver FAS gene expression and FAS levels. METHODS: A total of 25 male Wistar rats divided into five groups: (1) Standard diet (n); (2) high fat and fructose diet (HFFD); (3) HFFD have given beet 6%-contained standard diet (B1); (4) HFFD have given beet 9%-contained standard diet (B2), and (5) HFFD have given beet 12%-contained standard diet (B3). The HFFD was given to rats in the 2, 3, 4, and 5 group diets for 8 weeks? and then 3, 4, and 5 groups received beet-contained standard diet for 6 weeks. At the end of the intervention, FAS levels were measured (please specify where it was measured from) using the ELISA method, liver FAS gene expression was analyzed by quantitative polymerase chain reaction, and triglyceride (TG) levels were determined by the colorimetric method. RESULTS: The beet-substituted diet significantly suppressed the hepatic FAS gene expression and decreased the serum FAS levels in rats previously given HFFD (p < 0.05). The expression of the FAS gene showed a significant positive correlation with the levels of FAS serum (p < 0.05), and also with the hepatic TG levels but not significant (p > 0.05). Substitution of beet 9% in diet gives the best effect in hepatic FAS gene expression and the serum FAS levels. CONCLUSIONS: The diet contained beet 9% was seen as a necessary physiological dose to improve the effects of high-fat and diet fructose diet through suppressing FAS gene expression and a decreased serum FAS levels.

scholarly journals Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells

2010 ◽  
Vol 6 (1) ◽  
pp. 63-69 ◽  
Author(s):  
Maria Notarnicola ◽  
Simona Pisanti ◽  
Valeria Tutino ◽  
Domenica Bocale ◽  
Maria Teresa Rotelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Fatty Acid ◽  
Olive Oil ◽  
Cancer Cells ◽  
Fatty Acid Synthase ◽  
Human Colorectal Cancer ◽  
Colorectal Cancer Cells ◽  
Human Colorectal Cancer Cells ◽  
Expression And Activity

Regulation of the SREBP transcription factors by mTORC1

2011 ◽  
Vol 39 (2) ◽  
pp. 495-499 ◽  
Author(s):  
Caroline A. Lewis ◽  
Beatrice Griffiths ◽  
Claudio R. Santos ◽  
Mario Pende ◽  
Almut Schulze
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Target Genes ◽  
De Novo ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Mammalian Target Of Rapamycin ◽  
Lipid Biosynthesis ◽  
De Novo Lipogenesis ◽  
Genes Encoding

In recent years several reports have linked mTORC1 (mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs (sterol-regulatory-element-binding proteins). SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis. Lipid metabolism is perturbed in some diseases and SREBP target genes, such as FASN (fatty acid synthase), have been shown to be up-regulated in some cancers. We have previously shown that mTORC1 plays a role in SREBP activation and Akt/PKB (protein kinase B)-dependent de novo lipogenesis. Our findings suggest that mTORC1 plays a crucial role in the activation of SREBP and that the activation of lipid biosynthesis through the induction of SREBP could be part of a regulatory pathway that co-ordinates protein and lipid biosynthesis during cell growth. In the present paper, we discuss the increasing amount of data supporting the potential mechanisms of mTORC1-dependent activation of SREBP as well as the implications of this signalling pathway in cancer.

scholarly journals Gene expression pattern of acetyl-coA carboxylase alpha, fatty acid synthase, and stearoyl-CoA desaturase in pregnant Barki sheep under complete feed deprivation

2019 ◽  
pp. 8-13
Author(s):  
Ahmed El-Sayed ◽  
Ahmed Ateya ◽  
Mohamed Hamed ◽  
Sherif Shoieb ◽  
Hussam Ibrahim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Expression Pattern ◽  
Fatty Acid Synthase ◽  
Mrna Level ◽  
Gene Expression Pattern ◽  
Acetyl Coa Carboxylase ◽  
Down Regulation ◽  
Feed Deprivation ◽  
Stearoyl Coa Desaturase

Objective: To assess the mRNA level of acetyl CoA carboxylase alpha (ACACA), fatty acid synthase (FASN), and stearoyl-CoA desaturase (SCD) by means of real-time PCR in Barki sheep subjected to complete feed deprivation. Design: Controlled study. Animals: Seven healthy pregnant ewes. Procedures: Ewes were subjected to complete feed deprivation with ad libitum water for five consecutive days. Venous blood samples were collected from each ewe before (zero time) and on the fifth day post-deprivation of feed for measurement of the mRNA level of ACACA, FASN, and SCD and assessment of serum metabolic profile parameters. Results: On the fifth day post-fasting, the gene expression pattern of ACACA, FASN, SCD genes showed a significant (p < 0.05) down regulation in comparison with pre-deprivation of feed. There was a significant (p < 0.05) increase in the serum level of non-esterified fatty acids (NEFA), beta-hydroxyl buteric acid (BHBA), and triglycerides in pregnant ewes in the fifth day post-fasting in comparison with pre-deprivation of feed. On the other hand, there was a significant (p < 0.05) decrease in the level of glucose, cholesterol, and insulin in pregnant ewes in the fifth day post-fasting compared with pre-deprivation of feed. On histopathology, liver showed marked heptic steatosis in midzonal and periportal area, with formation of small fatty cysts in liver lobule. There was a positive correlation between leptin and insulin (r = 0.996; p < 0.01), BHB and leptin (r = 0.951; p < 0.05) and glucose and SCD (r = 1.0, p < 0.01). However, there was a negative correlation between FASN and NEFA (r = - 0.991; p < 0.05), FASN and leptin (r = -0.683; p < 0.05) and FASN and cholesterol (r = - 0.82; p < 0.05). Conclusion and clinical relevance: Pregnant Barki ewes can clinically tolerate complete feed deprivation for five days, with down regulation of ACACA, FASN, SCD genes and presence of marked metabolic changes. Therefore, metabolic monitoring is warranted to predict the early changes associated with feed deprivation under different stressful conditions.

scholarly journals Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

2021 ◽  
Author(s):  
Caterina Bartolacci ◽  
Cristina Andreani ◽  
Goncalo Dias do Vale ◽  
Stefano Berto ◽  
Margherita Melegari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Fatty Acid ◽  
Metabolic Networks ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Genetically Engineered ◽  
De Novo Lipogenesis ◽  
Main Process

Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

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