ATP-dependent binding cassette (ABC) transporters are a family of transmembrane proteins that pump a variety of hydrophobic compounds across cellular and subcellular barriers and are implicated in human diseases such as cancer and atherosclerosis. Inhibition of ABC transporter activity showed promise in early preclinical studies; however, the outcomes in clinical trials with these agents have not been as encouraging. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate genes involved in fat and glucose metabolism, and inflammation. Activation of PPAR signaling is also reported to regulate ABC gene expression. This suggests the potential of PPAR medicines as a novel means of controlling ABC transporter activity at the transcriptional level. This paper summarizes the advances made in understanding how PPAR medicines affect ABC transporters, and the potential implications for impacting on human diseases, in particular with respect to cancer and atherosclerosis. 1. Introduction Harnessing the energy released from adenosine triphosphate (ATP) hydrolysis, ATP-dependent binding cassette (ABC) transporters shuttle a wide range of substrates, including lipids, metabolites, and xenobiotics, across biological membranes in order to maintain normal cell metabolism. They represent the largest family of transmembrane proteins in humans, comprising 49 ABC genes, and are best reviewed elsewhere [1–3]. These genes are subdivided among seven subfamilies (A-G) based on sequence and structural homology and are highly conserved among eukaryotic species, suggesting that most appeared early in metazoan evolution [4]. The proteins encoded by ABC genes consist of two distinct domains: a transmembrane domain that recognizes specific compounds and transports them across cellular and subcellular barriers and a nucleotide-binding domain where ATP hydrolysis occurs to yield energy for substrate transport [5]. Typically, ABC proteins are unidirectional transporters expressed at the cell membrane, which move hydrophobic molecules internally for metabolic pathways, or externally for elimination from the cell and/or use by other tissues and organs. Thus, ABC transporters play important roles in a range of human physiologic, toxicologic, and pathologic functions. With respect to the latter, many preclinical reports that show promise in terms of regulating ABC transporters to overcome chemotherapeutic drug resistance in tumours, or modify lipid homeostasis in order to reduce atherosclerotic risk, have not achieved the same level of
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