Mechanisms of Gene Regulation by Fatty Acids

Nutrition, Metabolism and Genomics Group, Wageningen University, the Netherlands.
Advances in Nutrition (Impact Factor: 4.71). 03/2012; 3(2):127-34. DOI: 10.3945/an.111.001602
Source: PubMed

ABSTRACT Consumption of specific dietary fatty acids has been shown to influence risk and progression of several chronic diseases, such as cardiovascular disease, obesity, cancer, and arthritis. In recent years, insights into the mechanisms underlying the biological effects of fatty acids have improved considerably and have provided the foundation for the emerging concept of fatty acid sensing, which can be interpreted as the property of fatty acids to influence biological processes by serving as signaling molecules. An important mechanism of fatty acid sensing is via stimulation or inhibition of DNA transcription. Here, we focus on fatty acid sensing via regulation of gene transcription and address the role of peroxisome proliferator-activated receptors, sterol regulatory element binding protein 1, Toll-like receptor 4, G protein-coupled receptors, and other putative mediators.

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Available from: Sander Kersten, Sep 28, 2015
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    • "For instance, FASN could be involved in the control of FA synthesis and oxidation through a direct effect on the concentration of malonyl-CoA, which was shown to help control lipid metabolism through inhibition (allosteric ) of β-oxidation by carnitine palmitoyltransferase 1 (CPT1; Saggerson, 2008; Foster, 2012). In addition, FASN also helps generate ligands for transcription regulators, including peroxisome proliferator–activated receptors (PPAR; Chakravarthy et al., 2009, Georgiadi and Kersten, 2012), sterol-regulatory element binding protein 1 (SREBP1), hepatocyte nuclear factor 4a (HNF4α), NF-E2–related factor-2 (NRF2), and toll-like receptor 4 (TLR4; Georgiadi and Kersten, 2012), all of which are important for lipid metabolism regulation. Fatty acid synthase also may affect protein activity indirectly , e.g., endothelial nitric-oxide synthase, through palmitoylation (Wei et al., 2011). "
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    ABSTRACT: The role of fatty acid synthase (FASN) on de novo fatty acid synthesis has been well established. In monogastrics, unlike acetyl-coenzyme A carboxylase, FASN is primarily controlled at the transcriptional level. However, no data exist on ruminant mammary cells evaluating effects of FASN knockdown on mRNA expression of lipogenic genes. Inhibition of FASN in mammary cells by C75-mediated interference, a synthetic inhibitor of FASN activity, and short hairpin RNA-mediated interference markedly reduced cellular triglyceride content at least in part by decreasing the expression of genes related to triglyceride synthesis (GPAT, AGPAT6, and DGAT2) and enhancing the expression of lipolysis-related genes (ATGL and HSL). Consistent with the markedly lower expression of genes related to lipid droplet formation and secretion (TIP47, ADFP, BTN1A1, and XDH), cellular lipid droplets also were reduced sharply after incubation with C75 or adenovirus-short-hairpin-RNA. The results underscored the essential role of FASN in the overall process of milk-fat formation in goat mammary epithelial cells. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
    Journal of Dairy Science 02/2015; 98(5). DOI:10.3168/jds.2014-8202 · 2.57 Impact Factor
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    • ", 2011 ) . As such , we chose to examine PPARα , anoth - er key regulator in adipogenesis ( Georgiadi and Kersten , 2012 ) . The expression of all 3 genes was affected by diet ( P ≤ 0 . "
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    ABSTRACT: Knowledge of the molecular mechanisms which regulate ovine adipogenesis is very limited. MicroRNAs (miRNAs) have been reported as one of the regulatory mechanisms of adipogenesis. This study aimed to compare the expression of miRNAs related to ovine adipogenesis in different adipose depots and to investigate whether their expression is affected by dietary fatty acid composition. We also investigated the role of miRNA in adipogenic gene regulation. Subcutaneous and visceral adipose tissue samples were collected at slaughter from twelve Canadian Arcott lambs fed a barley-based finishing diet where an algae meal (DHA-G, Schizochytrium spp.) replaced flax oil and barley grain at 0 or 3% DM (n = 6). Total RNA from each tissue was subjected to qRT-PCR analysis to determine the expression of 15 selected miRNAs including 11 identified from bovine adipose tissues and 4 conserved between bovine and ovine species. miRNAs were differentially expressed according to diet in each tissue depot (miR-142-5p and -376d in visceral and miR-142-5p, -92a and -378 in subcutaneous adipose tissue; P ≤ 0.05) and in each tissue depot depending on diet (miR-101, -106, -136, -16b, -196a-1, -2368*, -2454, -296, -376d, -378 and -92a in both control and DHA-G diets, and miR-478 in control; P ≤ 0.05). Six miRNA were subjected to functional analysis and three genes of interest (ACSL1, PPARα and C/EPBα) were validated by qRT-PCR. Both diet and tissue depot affected expression levels of all three genes (P < 0.05). miR-101, -106 and -136 were negatively correlated with their respective predicted gene targets C/EBPα, PPARα and ACSL1 in subcutaneous adipose tissue of lambs fed DHA-G. Yet, miR-142-5p and miR-101 showed no correlation with ACSL1 or C/EBPα. The variability in expression patterns of miRNAs across adipose depots reflects the tissue specific nature of adipogenic regulation. Although the examined miRNAs appear to be conserved across ruminant species, our results indicate the presence of ovine specific regulatory mechanisms which can be influenced by diet.
    Journal of Animal Science 06/2014; 92(8). DOI:10.2527/jas.2014-7710 · 2.11 Impact Factor
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    • "The high rate of de novo synthesis generates essential lipids that are critical for the formation of cell membrane and produces extra energy for cancer proliferation and progression [22] [25] [42]. In contrast to fatty acid synthesis being downregulated in most normal human tissues, precancerous lesion and cancer cells upregulate fatty acid synthesis resulting in the high expression of FASN independent of dietary fat and independent of hormonal regulation in breast cancer (Figure 1) [17] [43]. "
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    ABSTRACT: Molecular targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells process a fundamental change in its bioenergetic metabolism from normal cells on an altered lipid metabolism, also known as the de novo fatty acid synthesis, for sustaining their high proliferation rates. Fatty acid synthesis is now associated with clinically aggressive tumor behavior and tumor cell growth and has become a novel target pathway for chemotherapy development. Although the underlying mechanisms of the altered de novo fatty acid synthesis still remains unclear, recent progress has shown that by targeting Fatty acid synthase (FASN), a key enzyme that catalyzes the synthesis of endogenous long chain fatty acid could be a critical target for drug discovery. However, relatively few FASN inhibitors have been discovered. With the long history of clinical practices and numerous histological case study reports, traditional Chinese medicine enjoys an important role in seeking bioactive anticancer natural compounds. Herein, we will give an overall picture of the current progress of molecular targeted therapy in cancer fatty acid synthesis, describe the advances in the research on natural products-derived FASN inhibitors and their potential for enhancing our understanding of fatty acids in tumor biology, and may provide new therapeutic moieties for breast cancer patient care.
    Evidence-based Complementary and Alternative Medicine 03/2014; 2014(9):232946. DOI:10.1155/2014/232946 · 1.88 Impact Factor
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