Control of Gene Expression by Fatty Acids

Abstract

The last decade provided evidence that major (glucose, fatty acids, amino acids) or minor (iron, vitamin, etc.) dietary constituents regulated gene expression in an hormonal-independent manner. This review focuses on molecular mechanisms by which fatty acids control the expression genes encoding regulatory protein involved in their own metabolism. Nonesterified fatty acids or their CoA derivatives seem to be the main signals involved in the transcriptional effect of long-chain fatty acids. The effects of fatty acids are mediated either directly owing to their specific binding to various nuclear receptors (PPAR, LXR, HNF-4alpha) leading to changes in the trans-activating activity of these transcription factors, or indirectly as the result of changes in the abundance of regulatory transcription factors (SREBP-1c, ChREBP, etc.). The relative contribution of each transcription factor in fatty acid-induced positive or negative gene expression is discussed.

Free Fatty Acids Repress the GLUT4 Gene Expression in Cardiac Muscle via Novel Response Elements

“…Sequences for several factors were revealed, including those for PPAR␥, HNF4␣, HNF1, SP1, and nuclear factor Y. HNF4␣ is a member of the steroid/thyroid hormone receptor superfamily, and it seemed a logical candidate for a mediator of FFA regulation of GLUT4 because it has been demonstrated that long chain fatty acids directly modulate the transcriptional activity of the HNF4␣ transcription factor by binding to its ligand-binding domain (39). In light of our present data and work by others (22,23), PPAR␥ seemed another good candidate, because this nuclear receptor was also found to bind with high affinity to long chain fatty acids. However, no complex supershift could be detected in our hands with either anti-PPAR␥ or anti-HNF4␣ antibodies, despite the presence of consensus binding motifs for these factors.…”

“…22). Recently, it was found that HNF4 competes with PPAR␥ both by binding to FFA ligands on the one hand and by binding to the DNA binding sites of the DR1-type PPRE on the other (22). A computer analysis revealed that consensus binding motifs for either PPAR or HNF4 or both exist in each of the FFA-RE we identified on the GLUT4 promoter, which may explain in part the complex regulation of GLUT4 and PPAR␥ gene expression by FIGURE 8.…”

“…The most prominent among these are PPAR, HNF, sterol regulatory element-binding protein, nuclear factor Y, and SP1 (reviewed in Ref. 22). Recently, it was found that HNF4 competes with PPAR␥ both by binding to FFA ligands on the one hand and by binding to the DNA binding sites of the DR1-type PPRE on the other (22).…”

Regulation of gene transcription by fatty acids

“…Binding of saturated fatty acyl-CoAs activates HNF-4a while unsaturated fatty acyl-CoAs inhibit HNF-4a transcriptional activity. HNF-4a binds to DR1 response elements as a homodimer and may potentially compete with PPAR/RXR heterodimers for DNA binding (Pé gorier et al, 2004). It has also been shown that fibrates can be converted to CoA-thioesters that bind HNF-4a to inhibit its transcriptional activity, thus providing another level of competition between HNF-4a and PPARs (Hertz et al, 2001).…”

“…The role of fatty acids as substrates in these pathways and their conversion to eicosanoids, with different levels of activity depending on the structure of the parent molecule, represents two mechanisms whereby they exert their effect. However, the last decade has seen a growing body of evidence to suggest that fatty acids and/or their derivatives also have direct effects on the expression of genes for proteins regulating carbohydrate and lipid metabolism (Jump and Clarke, 1999;Pé gorier et al, 2004;Jump et al, 2005;Sampath and Ntambi, 2005;Davidson, 2006). This review will explore the emerging mechanisms whereby dietary fatty acids can directly influence gene expression.…”