A ROLE FOR THIAMINE IN THE REGULATION OF FATTY ACID AND CHOLESTEROL BIOSYNTHESIS IN CULTURED CELLS OF NEURAL ORIGIN

Acetyl-CoA carboxylase (ACC), an important enzyme in fatty acid biosynthesis and a regulator of fatty acid oxidation, is present in at least two isoenzymic forms in rat and human tissues. Previous work has established the existence of a 265000 Da enzyme in both the rat and human (RACC265; HACC265) and a higher-molecular-mass species (275000–280000 Da) in the same species (RACC280; HACC275). An HACC265 gene has previously been localized to chromosome 17. In the present study, we report cloning of a partial-length human cDNA sequence which appears to correspond to HACC275 and its rat homologue, RACC280, as judged by mRNA tissue distribution and cell-specific regulation of mRNA/protein expression. The gene encoding this isoenzymic form of ACC has been localized to the long arm of human chromosome 12. Thus, ACC is represented in a multigene family in both rodents and humans. The newly discovered human gene and its rat homologue appear to be under different regulatory control to the HACC265 gene, as judged by tissue-specific expression in vivo and by independent modulation in cultured cells in vitro.

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TAMI-62. METHIONINE METABOLISM CLOSELY RELATED WITH SELF-RENEW, PLURIPOTENCY AND CELL DEATH IN GICS THROUGH MODIFICATION OF CHOLESTEROL BIOSYNTHESIS, RIBOSOMAL RNA AND AUTOPHAGY

Neuro-Oncology ◽

10.1093/neuonc/noab196.844 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi211-vi211

Author(s):

Kiyotaka Yokogami ◽

Hideo Takeshima

Keyword(s):

Stem Cells ◽

Cell Death ◽

Ribosomal Rna ◽

Cell Activation ◽

Cultured Cells ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Dna Demethylation ◽

Methionine Metabolism ◽

Starting Point

Abstract Glioma initiating cells (GICs) are the source of glioma cells that have the ability to self-renew and pluripotency, which are treatment-resistant, starting point for relapse and eventual death despite multimodality therapy. Since high accumulation is observed in 11cMet-PET at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. We cultured cells in methionine-deprived culture medium and performed a comprehensive analysis, and found that methionine depletion markedly decreased proliferation and increasing cell death of GICs. Decreased SAM, which is synthesized intracellularly catalyzed by methionine adenosyltransferase (MAT) using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotentcy of stem cells, (iii) decreased expression of the core-genes and pluripotent marker of stem cells, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2 and FOXM1, (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, snoRNA guiding the pseudouridylation of 28S ribosomal RNA, which has crucial role for translation and (vi) possible connection between methionine metabolism and pluripotency, protein synthesis through cholesterol metabolism: SREBF2-FOXM1 and ACA43 axis, respectively. (vii) Disruption of autophagy by insufficient formation of macroautophagosomes. In conclusion, methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis, ribosomal RNA and autophagy.

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Regulation of the SREBP transcription factors by mTORC1

Biochemical Society Transactions ◽

10.1042/bst0390495 ◽

2011 ◽

Vol 39 (2) ◽

pp. 495-499 ◽

Cited By ~ 42

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.

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Phytohormones Regulate the Non-Redundant Response of ω-3 Fatty Acid Desaturases to Low Temperatures in Chorispora Bungeana

10.21203/rs.3.rs-719872/v1 ◽

2021 ◽

Author(s):

Yulan Shi ◽

Sizhong Yang ◽

Xiule Yue ◽

Zhixing Zhao ◽

Lizhe An

Keyword(s):

Fatty Acids ◽

Abscisic Acid ◽

Fatty Acid ◽

Stress Response ◽

Low Temperatures ◽

Cultured Cells ◽

Temperature Decrease ◽

Fatty Acid Desaturases ◽

Cold Environments ◽

Chorispora Bungeana

Abstract To explore the contribution of ω-3 fatty acid desaturases (FADs) to cold stress response in a special cryophyte, Chorispora bungeana (C. bungeana), two plastidial ω-3 FAD genes (CbFAD7 and CbFAD8) were cloned and verified in a Arabidopsis fad7fad8 mutant, before being compared with the microsomal ω-3 FAD gene (CbFAD3) on expression profile. Though these genes were expressed in all tested tissues of C. bungeana, CbFAD7 and CbFAD8 have the highest expression in leaves, while CbFAD3 was mostly expressed in non-green tissues. Low temperatures (4, 0 and -4 ℃) resulted in significant increases in trienoic fatty acids (TAs, mainly C18:3), which were consistent with the non-redundant expression of CbFAD3 and CbFAD8 in suspension-cultured cells, and the coordination of CbFAD7 and CbFAD8 in leaves. Furthermore, the contribution of CbFAD8 increased as temperature decrease in the two tissues. Our data revealed that jasmonie acid and brassinosteroids participated in the cold-responsive expression of these genes in both tissues, and the pyhtohormone regulation in leaves was more complicated with the participation of abscisic acid and gibberellin. These results point to the hormone-regulated non-redundant contribution of ω-3 CbFADs to maintain appropriate level of TAs under low temperatures, which help C. bungeana survive in cold environments.

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Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans

Gut ◽

10.1136/gutjnl-2018-317581 ◽

2019 ◽

Vol 69 (1) ◽

pp. 177-186 ◽

Cited By ~ 20

Author(s):

Li Che ◽

Wenna Chi ◽

Yu Qiao ◽

Jie Zhang ◽

Xinhua Song ◽

...

Keyword(s):

Fatty Acid ◽

Cell Lines ◽

Knockout Mice ◽

Fatty Acid Synthase ◽

De Novo ◽

Therapeutic Option ◽

Regulatory Element ◽

Cholesterol Biosynthesis ◽

Dominant Negative ◽

Comparative Genomic

ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC).DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specificFasnknockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type andFasnknockout mice. Human HCC cell lines were used for in vitro studies.ResultsAblation ofFasnsignificantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged inFasnknockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss ofFasnpromoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis inFasnknockout mice. Similarly, silencing ofFASNresulted in increasedSREBP2activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR)expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture.ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.

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Distinct Transcriptional Signatures of Monocytes Treated with α-linolenic Acid and Docosahexaenoic Acid

Current Developments in Nutrition ◽

10.1093/cdn/nzaa058_028 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1270-1270

Author(s):

Samantha Pauls ◽

Christopher Pascoe ◽

Lisa Rodway ◽

Carla Taylor ◽

Harold Aukema ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Docosahexaenoic Acid ◽

Linolenic Acid ◽

Cholesterol Biosynthesis ◽

Interaction Network ◽

Principal Component ◽

Change Analysis ◽

Future Studies ◽

Engineering Research

Abstract Objectives Docosahexaenoic acid (DHA) can be obtained directly from the diet or produced by elongation and desaturation of α-linolenic acid (ALA). Both are proposed to reduce inflammation associated with obesity, however, fewer studies have investigated ALA. The objective of this study was to evaluate the gene expression changes in monocytes induced by each fatty acid and to compare the predicted functional outcomes. Methods RNA was extracted from THP-1 monocytes treated with ALA, DHA or vehicle for 48 h and then transcriptomics profiles were assessed by microarray. Multiple tools were used for data interpretation, including fold change analysis, Principal Component Analysis (PCA), Variable Importance Projection (VIP), Ingenuity Pathway Analysis (IPA) and Network Analyst. Results We found that the ALA and DHA treatments produced distinct profiles with many individual genes making small contributions to the separation between groups. Relative to vehicle treatment, many downregulated targets were similarly affected by both ALA and DHA. Several of these downregulated genes are involved in cholesterol synthesis and are regulated by miR-335–5p, a microRNA upregulated by both treatments. Consistently, IPA predicted similar pathways and functions are decreased by ALA and DHA, most notably cholesterol biosynthesis. In contrast, ALA and DHA upregulated unique gene sets and in agreement IPA predicted each treatment would activate distinct pathways and functions. ALA was strongly and uniquely predicted to increase infection responses while only DHA was predicted to increase oxidative phosphorylation. Finally, analysis of the protein-protein interaction network involving the genes modified by each fatty acid treatment allowed us to predict the most functionally important gene targets, which will be tested in future studies. Conclusions These analyses have revealed both unique and overlapping effects of ALA and DHA on the monocyte gene expression profile, providing further evidence that they have distinct bioactivities. Many novel predictions were made and these will form the basis for future studies investigating the effects of ALA and DHA on human physiology. Funding Sources Natural Sciences and Engineering Research Council of Canada; Canadian Institutes of Health Research.

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