Article

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.

Download full-text

Full-text

Available from: Sander Kersten
  • Source
    • "There also are several non-LdNR TF that control the expression of genes when activation by nutrients; however , such activation is not direct but mediated by other factors. These include sterol regulatory element-binding proteins sterol regulatory element-binding protein (SREBP1; gene name SREBF1), which are affected by long-chain fatty acids (LCFA; Georgiadi and Kersten, 2012) and glucose (Uttarwar et al., 2012); Spot14 or thyroid hormone responsive protein (THRSP), which is affected by polyunsaturated fatty acids (PUFA; Cunningham et al., 1998); carbohydrate responsive element binding protein (ChREBP; gene name MLXIPL), "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nutrigenomics in dairy cows is a relatively new area of research. It is defined as the study of the genome wide influences of nutrition altering the expression of genes. Dietary compounds affect gene expression directly or indirectly via interactions with transcription factors. Among those, the most relevant for nutrigenomics are ligand-dependent nuclear receptors, especially peroxisome proliferator-activated receptors (PPAR) and liver X receptor. Among other transcription factors, a prominent nutrigenomic role is played by the sterol regulatory element-binding protein 1 (SREBP1). Data from studies on dairy cows using gene expression and gene reporters among the main molecular methods used to study nutrigenomics in dairy cows are indicative of a network of multiple transcription factors at play in controlling the nutrigenomic responses. Fatty acids, AA, and level of feed and energy intake have the strongest nutrigenomic potential. The effect of t10,c12 CLA on depressing milk fat synthesis via inhibition of SREBP1 was among the first and likely the best-known nutrigenomic example in dairy cows. Although long-chain fatty acids (LCFA) are clearly the most potent, a nutrigenomic role for short-chain fatty acids is emerging. Available data indicate that saturated compared with unsaturated LCFA have a more potent nutrigenomic effect in vitro, likely through PPAR. In vivo, the effect of saturated LCFA is more modest, with contrasting effects among tissues. Nutrigenomic effects of AA are emerging, particularly for the regulation of milk protein synthesis–associated genes. The level of energy in the diet has a strong and broad nutrigenomic effect and appears to “prime” tissue metabolism, particularly liver. We are at the frontier of the nutrigenomics era in ruminants and initial data strongly indicate that this scientific branch (and spinoffs such as nutriepigenomics) can play a critical role in future strategies to better feed dairy cattle.
    Full-text · Article · Nov 2015 · Journal of Animal Science
  • Source
    • "These include sterol regulatory element-binding proteins sterol regulatory element-binding protein (SREBP1; gene name SREBF1), which are affected by long-chain fatty acids (LCFA; Georgiadi and Kersten, 2012) and glucose (Uttarwar et al., 2012); Spot14 or thyroid hormone responsive protein (THRSP), which is affected by polyunsaturated fatty acids (PUFA; Cunningham et al., 1998); carbohydrate responsive element binding protein (ChREBP; gene name MLXIPL), which is activated indirectly by glucose 6-phosphate and xylulose-5-phosphate (Li et al., 2006; Oosterveer and Schoonjans, 2014); and CCAAT/enhancer-binding protein, activating transcription factor 4, and nuclear factor kappa-light-chain-enhancer of activated B cells, which respond to AA deprivation (Kilberg et al., 2012). Georgiadi and Kersten (2012) recently provided a review of TF involved in sensing fatty acids also including , besides the ones reported above, Toll-like receptor 4 and nuclear factor erythroid 2-related factor 2. Few of the above TF have been studied in dairy cattle as potential targets for nutrigenomic approaches. In the following sections, we provide an overview of the relatively few investigated LdNR and non-LdNR TF and their nutrigenomic roles in dairy cows. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nutrigenomics in dairy cows is a relatively new area of research. It is defined as the study of the genome-wide influences of nutrition altering the expression of genes. Dietary compounds affect gene expression directly or indirectly via interactions with transcription factors. Among those, the most relevant for nutrigenomics are ligand-dependent nuclear receptors, especially peroxisome proliferator-activated receptors (PPAR) and liver X receptor. Among other transcription factors, a prominent nutrigenomic role is played by the sterol regulatory binding protein 1 (SREBP1). Data from studies on dairy cows using gene expression and gene reporters among the main molecular methods used to study nutrigenomics in dairy cows, are indicative of a network of multiple transcription factors at play in controlling the nutrigenomic responses. Fatty acids, amino acids, and level of feed and energy intake have the strongest nutrigenomic potential. The effect of t10,c12-conjugated linoleic acid on depressing milk fat synthesis via inhibition of SREBP1 was among the first and likely the best-known nutrigenomic example in dairy cows. Although long-chain fatty acids (LCFA) are clearly the most potent, a nutrigenomic role for short-chain fatty acids is emerging. Available data indicate that saturated compared with unsaturated LCFA have a more potent nutrigenomic effect in vitro, likely through PPAR. In vivo the effect of saturated LCFA is more modest with contrasting effects among tissues. Nutrigenomic effects of amino acids are emerging, particularly for the regulation of milk protein synthesis-associated genes. The level of energy in the diet has a strong and broad nutrigenomic effect and appears to ‘prime’ tissue metabolism, particularly liver. We are at the frontier of the nutrigenomics era in ruminants and initial data strongly indicate that this scientific branch (and spinoffs such as nutriepigenomics) can play a critical role in future strategies to better feed dairy cattle.
    Full-text · Article · Jul 2015 · Journal of Animal Science
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Feb 2015 · Journal of Dairy Science
Show more