Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

2012 ◽  
Vol 302 (12) ◽  
pp. E1461-E1471 ◽  
Author(s):  
Takeshi Kobayashi ◽  
Ko Fujimori
Keyword(s):  
Fatty Acids ◽  
Target Genes ◽  
Mrna Level ◽  
Peroxisome Proliferator ◽  
Long Chain Fatty Acids ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipogenic Genes ◽  
Pparγ Agonist ◽  
Long Chain ◽  
Chain Fatty Acids

Here, we show that Elovl3 (elongation of very long-chain fatty acids 3) was involved in the regulation of the progression of adipogenesis through activation of peroxisome proliferator-activated receptor (PPAR)γ in mouse adipocytic 3T3-L1 cells. The expression of the Elovl3 gene increased during adipogenesis, the expression pattern of which was similar to that of the PPARγ gene. Troglitazone, a PPARγ agonist, enhanced Elovl3 expression in adipocytes, as it did that of other PPARγ target genes. Promoter-reporter analysis demonstrated that three PPAR-responsive elements in the Elovl3 gene promoter had the potential to activate its expression in 3T3-L1 cells. Moreover, a chromatin immunoprecipitation assay revealed that PPARγ bound these PPAR-responsive elements of the Elovl3 promoter. When the Elovl3 mRNA level was suppressed by its siRNAs, the level of intracellular triglycerides was significantly decreased, and the expression levels of adipogenic, lipolytic, and lipogenic genes were also repressed. In a mammalian two-hybrid assay, C18:1 and C20:1 very long-chain fatty acids (VLCFAs), which are the products of Elovl3 and activated PPARγ function. In addition, these same VLCFAs could prevent the Elovl3 siRNA-mediated suppression of adipogenesis by enhancing the expression of adipogenic, lipolytic, and lipogenic genes in adipocytes. Moreover, this VLCFAs-mediated activation was repressed by a PPARγ antagonist. These results indicate that the expression of the Elovl3 gene was activated by PPARγ during adipogenesis. Elovl3-produced C18:1 and C20:1 VLCFAs acted as agonists of PPARγ in 3T3-L1 cells. Thus, the Elovl3-PPARγ cascade is a novel regulatory circuit for the regulation of adipogenesis through improvement of PPARγ function in adipocytes.

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 Hepatic Peroxisomal Fatty Acid β-Oxidation Is Regulated by Liver X Receptor α

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5380-5387 ◽  
Author(s):  
Tonghuan Hu ◽  
Patricia Foxworthy ◽  
Angela Siesky ◽  
James V. Ficorilli ◽  
Hong Gao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Liver Steatosis ◽  
Liver X Receptor ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Long Chain Fatty Acids ◽  
Lxr Agonists ◽  
Long Chain ◽  
Chain Fatty Acids

Peroxisomes are the exclusive site for the β-oxidation of very-long-chain fatty acids of more than 20 carbons in length (VLCFAs). Although the bulk of dietary long-chain fatty acids are oxidized in the mitochondria, VLCFAs cannot be catabolized in mitochondria and must be shortened first by peroxisomal β-oxidation. The regulation of peroxisomal, mitochondrial, and microsomal fatty acid oxidation systems in liver is mediated principally by peroxisome proliferator-activated receptor α (PPARα). In this study we provide evidence that the liver X receptor (LXR) regulates the expression of the genetic program for peroxisomal β-oxidation in liver. The genes encoding the three enzymes of the classic peroxisomal β-oxidation cycle, acyl-coenzyme A (acyl-CoA) oxidase, enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase, are activated by the LXR ligand, T0901317. Accordingly, administration of T0901317 in mice promoted a dose-dependent and greater than 2-fold increase in the rate of peroxisomal β-oxidation in the liver. The LXR effect is independent of PPARα, because T0901317-induced peroxisomal β-oxidation in the liver of PPARα-null mice. Interestingly, T0901317-induced peroxisomal β-oxidation is dependent on the LXRα isoform, but not the LXRβ isoform. We propose that induction of peroxisomal β-oxidation by LXR agonists may serve as a counterregulatory mechanism for responding to the hypertriglyceridemia and liver steatosis that is promoted by potent LXR agonists in vivo; however, additional studies are warranted.

scholarly journals Fine metabolic regulation in ruminants via nutrient–gene interactions: saturated long-chain fatty acids increase expression of genes involved in lipid metabolism and immune response partly through PPAR-α activation

2011 ◽  
Vol 107 (2) ◽  
pp. 179-191 ◽  
Author(s):  
Massimo Bionaz ◽  
Betsy J. Thering ◽  
Juan J. Loor
Keyword(s):  
Fatty Acids ◽  
Lipid Metabolism ◽  
Metabolic Regulation ◽  
Target Genes ◽  
Long Chain Fatty Acids ◽  
Response Data ◽  
Expression Of Genes ◽  
Gene Network Analysis ◽  
Long Chain ◽  
Chain Fatty Acids

Madin–Darby Bovine Kidney cells cultured with 150 μm of Wy-14 643 (WY, PPARα agonist) or twelve long-chain fatty acids (LCFA; 16 : 0, 18 : 0, cis-9–18 : 1, trans-10–18 : 1, trans-11–18 : 1, 18 : 2n-6, 18 : 3n-3, cis-9, trans-11–18 : 2, trans-10, cis-12–18 : 2, 20 : 0, 20 : 5n-3 and 22 : 6n-3) were used to uncover PPAR-α target genes and determine the effects of LCFA on expression of thirty genes with key functions in lipid metabolism and inflammation. Among fifteen known PPAR-α targets in non-ruminants, ten had greater expression with WY, suggesting that they are bovine PPAR-α targets. The expression of SPP1 and LPIN3 was increased by WY, with no evidence of a similar effect in the published literature, suggesting that both represent bovine-specific PPAR-α targets. We observed the strongest effect on the expression of PPAR-α targets with 16 : 0, 18 : 0 and 20 : 5n-3.When considering the overall effect on expression of the thirty selected genes 20 : 5n-3, 16 : 0 and 18 : 0 had the greatest effect followed by 20 : 0 and c9t11–18 : 2. Gene network analysis indicated an overall increase in lipid metabolism by WY and all LCFA with a central role of PPAR-α but also additional putative transcription factors. A greater increase in the expression of inflammatory genes was observed with 16 : 0 and 18 : 0. Among LCFA, 20 : 5n-3, 16 : 0 and 18 : 0 were the most potent PPAR-α agonists. They also affected the expression of non-PPAR-α targets, eliciting an overall increase in the expression of genes related to lipid metabolism, signalling and inflammatory response. Data appear to highlight a teleological evolutionary adaptation of PPAR in ruminants to cope with the greater availability of saturated rather than unsaturated LCFA.

scholarly journals Epigenomics and Lipidomics Integration in Alzheimer Disease: Pathways Involved in Early Stages

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1812
Author(s):  
Carmen Peña-Bautista ◽  
Lourdes Álvarez-Sánchez ◽  
Antonio José Cañada-Martínez ◽  
Miguel Baquero ◽  
Consuelo Cháfer-Pericás
Keyword(s):  
Fatty Acids ◽  
Alzheimer Disease ◽  
Target Genes ◽  
Differentially Expressed ◽  
Long Chain Fatty Acids ◽  
Targeted Analysis ◽  
Fatty Acids Metabolism ◽  
Positive Correlations ◽  
Long Chain ◽  
Chain Fatty Acids

Background: Alzheimer Disease (AD) is the most prevalent dementia. However, the physiopathological mechanisms involved in its development are unclear. In this sense, a multi-omics approach could provide some progress. Methods: Epigenomic and lipidomic analysis were carried out in plasma samples from patients with mild cognitive impairment (MCI) due to AD (n = 22), and healthy controls (n = 5). Then, omics integration between microRNAs (miRNAs) and lipids was performed by Sparse Partial Least Squares (s-PLS) regression and target genes for the selected miRNAs were identified. Results: 25 miRNAs and 25 lipids with higher loadings in the sPLS regression were selected. Lipids from phosphatidylethanolamines (PE), lysophosphatidylcholines (LPC), ceramides, phosphatidylcholines (PC), triglycerides (TG) and several long chain fatty acids families were identified as differentially expressed in AD. Among them, several fatty acids showed strong positive correlations with miRNAs studied. In fact, these miRNAs regulated genes implied in fatty acids metabolism, as elongation of very long-chain fatty acids (ELOVL), and fatty acid desaturases (FADs). Conclusions: The lipidomic–epigenomic integration showed that several lipids and miRNAs were differentially expressed in AD, being the fatty acids mechanisms potentially involved in the disease development. However, further work about targeted analysis should be carried out in a larger cohort, in order to validate these preliminary results and study the proposed pathways in detail.

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