Peroxisome Proliferator–Activated Receptors: A Critical Link among Fatty Acids, Gene Expression and Carcinogenesis

It has been known for many years that long-chain fatty acids derived from endogenous metabolism and/or nutrition can act as second messengers and regulators of cell signaling pathways. For example, fatty acids regulate the activity of protein kinase C (PKC) in a mechanism distinct from activation by diacylglycerol. Like PKC activators such as phorbol esters, essential fatty acids activate PKC and in doing so modulate the activity of growth factor receptors such as epidermal growth factor receptor (EGFR). Unsaturated fatty acids can inhibit GTPase activating protein, thereby quenching signals from p21-ras. These studies have shown that fatty acids can influence numerous signaling pathways and that these small lipophilic substances may be ancient second messengers. Fatty acids are also known modulators of the carcinogenic process, showing distinct tissue-specific pro- or anticancer effects. However, the reason for such a dichotomous effect on cellular processes has not been adequately described. In this article, the inclusion of a steroid hormone receptor-signaling pathway in mediating fatty acids' effects will be summarized. This signaling molecule has been deemed the peroxisome proliferator-activated receptor (PPAR) and has been extensively examined in regard to its response to xenobiotic, fatty acid-like chemicals (peroxisome proliferators, PP). PP, like fatty acids, activate PPAR and modulate tissue-specific responses. The goal of this review is to describe a potential role for PPAR in mediating the effects of fatty acids on gene expression, cell growth, differentiation and apoptosis.