Fatty acids: ancestral ligands and modern co-regulators of the steroid hormone receptor cell signalling pathway

Long chain fatty acids derived from endogenous metabolism and/or nutrition are regulators of cell signalling pathways. They can be lipid second messengers of signal transduction systems or modulators and regulators of intracellular signalling pathways such as those involved in the mechanism of action of steroid hormones. Fatty acids have been shown to activate gene transcription under the control of some evolutionarily primitive members of the steroid/thyroid superfamily of receptors. They may represent ancestral ligands of this superfamily of receptors. Fatty acids are also known to regulate the activity of protein kinases, particularly protein kinase C, and thereby phosphorylation of intracellular proteins involved in regulation of gene transcription. Fatty acids may be co-regulators in the cross-talk between membrane-triggered signal transduction and the intracellular steroid hormone signalling pathway. Fatty acids are known to affect either negatively and/or positively the binding of steroid hormones to their specific plasma transport proteins and their specific intracellular receptors and, very recently, fatty acids have also been shown to co-regulate glucocorticoid-dependent gene expression. The mechanism of action of steroid hormones will be used as an illustration of how fatty acids can intervene at different levels of cellular organization to regulate biological activity, with a focus on the glucocorticoid receptor.