Regulation of the Action of Steroid/Thyroid Hormone Receptors by Medium-chain Fatty Acids

Thurmond, Debbie C.; Baillie, Rebecca; Goodridge, Alan G.

doi:10.1074/jbc.273.25.15373

Cited by 17 publications

(14 citation statements)

References 45 publications

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“…As previously demonstrated for the malic enzyme promoter [47], we showed that hexanoate targets the TRE on the FAS promoter (Fig. 3b), inhibiting its transcriptional activity in the presence of insulin and T 3 .…”

Section: Discussionsupporting

confidence: 58%

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Akpa

Point

Sawadogo

et al. 2010

Lipids

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Fatty acid synthase (FAS) is responsible for the de novo synthesis of palmitate and stearate. This enzyme is activated by insulin and T(3), and inhibited by fatty acids. In this study, we show that insulin and T(3) have an inducing effect on FAS enzymatic activity, which is synergetic when both hormones are present. Octanoate and hexanoate specifically inhibit this hormonal effect. A similar inhibitory effect is observed at the level of protein expression. Transient transfections in HepG2 cells revealed that hexanoate inhibits, at least in part, FAS at a transcriptional level targeting the T(3) response element (TRE) on the FAS promoter. The effect of C6 on FAS expression cannot be attributed to a modification of insulin receptor activation or to a decrease in T(3) entry in the cells. Using bromo-hexanoate, we determined that hexanoate needs to undergo a transformation in order to have an effect. When incubating cells with triglyceride-hexanoate or carnitine-hexanoate, no effect on the enzymatic activity induced by insulin and T(3) is observed. A similar result was obtained when cells were incubated with betulinic acid, an inhibitor of the diacylglycerol acyltransferase. However, the incubation of cells with Triacsin C, a general inhibitor of acyl-CoA synthetases, completely reversed the inhibitory effect of hexanoate. Our results suggest that in hepatic cells, hexanoate needs to be activated into a CoA derivative in order to inhibit the insulin and T(3)-induced FAS expression. This effect is partially transcriptional, targeting the TRE on the FAS promoter.

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Section: Discussionsupporting

confidence: 58%

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Akpa

Point

Sawadogo

et al. 2010

Lipids

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“…Whether this observation has any physiological rele-vance remains an open question. Last but not least, in chick hepatocytes, it was shown that medium chain FAs can alter triiodothyronine or estrogen action without interfering with the binding of the respective receptors to their cognate DNA elements (49).…”

Section: In Search Of the Fa-responsive Transcription Factorsmentioning

confidence: 99%

Fatty Acid Regulation of Gene Transcription

Duplus¹,

Glorian²,

Forest

2000

Journal of Biological Chemistry

331

189

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“…The treatment of primary chicken hepatocytes with medium-chain fatty acids has been shown to reduce the transcription factor SREBP-1 at both the mRNA and protein level (Zhang et al 2003), which stands in direct contrast to insulin action in hepatocytes. Furthermore, medium-chain fatty acids have been shown to inhibit ligand-stimulated activity of thyroid hormone receptors (Thurmond et al 1998). In consequence, an increase in free medium-chain fatty acids in the liver could lead to perturbations in glucose and lipid metabolism, therefore adding to disease susceptibility.…”

Section: Resultsmentioning

confidence: 99%

Comparative Analyses of Disease Risk Genes Belonging to the Acyl-CoA Synthetase Medium-Chain (ACSM) Family in Human Liver and Cell Lines

et al. 2009

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The human ACSM1, 2A and B, 3, and 5 genes, located on chromosome 16p12-13, encode for enzymes catalyzing the activation of medium-chain length fatty acids. Association studies have linked several polymorphisms of these genes to traits of insulin resistance syndrome. In our study, ACSM transcripts showed 3 to >400-fold higher expression levels in human liver when compared to cell lines by qRT-PCR. This difference was also evident at the protein level, as shown for ACSM2. In liver, ACSM2 was the most abundant transcript, showing sixfold (vs. ACSM3) to >300-fold higher expression levels (vs. ACSM1). Mitochondrial localization of the ACSM2 protein and the presence of an N-terminal targeting sequence were shown by GFP-tagging. We have shown ACSM2B to be the predominant transcript in human liver, and genetic variations of this gene could therefore play an important role in disease susceptibility.

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Regulation of the Action of Steroid/Thyroid Hormone Receptors by Medium-chain Fatty Acids

Cited by 17 publications

References 45 publications

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Fatty Acid Regulation of Gene Transcription

Comparative Analyses of Disease Risk Genes Belonging to the Acyl-CoA Synthetase Medium-Chain (ACSM) Family in Human Liver and Cell Lines

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Regulation of the Action of Steroid/Thyroid Hormone Receptors by Medium-chain Fatty Acids

Cited by 17 publications

References 45 publications

Inhibition of Insulin and T3‐Induced Fatty Acid Synthase by Hexanoate

Inhibition of Insulin and T3‐Induced Fatty Acid Synthase by Hexanoate

Fatty Acid Regulation of Gene Transcription

Comparative Analyses of Disease Risk Genes Belonging to the Acyl-CoA Synthetase Medium-Chain (ACSM) Family in Human Liver and Cell Lines

Contact Info

Product

Resources

About

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate