Transcriptional Regulation of Peroxisome Proliferator–Activated Receptors and Liver X Receptors Luis Villacorta, PhD, Minerva T. Garcia-Barrio, PhD, and Yuqing E. Chen, MD, PhD Corresponding author Yuqing E. Chen, MD, PhD Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA. E-mail: echenum@umich.edu Current Atherosclerosis Reports 2007, 9:230–237 Current Medicine Group LLC ISSN 1523-3804 Copyright © 2007 by Current Medicine Group LLC Peroxisome proliferator–activated receptors (PPAR) and liver X receptors (LXR) regulate a plethora of biologic processes and key metabolic and physiologic events. Deregulation of their transcription and activity is commonly associated with dyslipidemic disorders, dia- betes, cancer, and cardiovascular disease. This review addresses recent advances in our understanding of the molecular mechanisms regulating transcription of these nuclear receptors. The heterogeneity of factors regulat- ing their transcription and activity suggests intricate regulatory networks that determine their tissue expres- sion pattern and their responses to pharmacologic agents. Understanding such mechanisms will facilitate unraveling their protective effects in disease as well as the design of effective targeted therapies. Introduction In 2002, expert scientists under the auspices of the National Institutes of Health joined forces to integrate different aspects of nuclear receptor (NR) research, evalu- ate current knowledge, and establish an open platform to formulate and validate new hypotheses and exploit emerging technologies such as genomics and proteomics to further advance the research on NRs. The result was the establishment of the Nuclear Receptor Signaling Atlas (NURSA) Consortium [1]. The success of the initiative underscores the importance of the role of NRs in a pleth- ora of biologic processes and establishes the basis of a systematic and multidisciplinary approach in NR research (for more information on the NURSA Consortium, visit their website at http://www.nursa.com). Forty-nine NRs have been described, each of them independently covering different (and/or overlapping) aspects of disease condi- tions, such as cancer, obesity, diabetes, and cardiovascular disease. In particular, among all NRs, the peroxisome proliferator–activated receptors (PPARs) and liver X receptors (LXRs) are considered a “nexus among nutri- tion, metabolism and infammation” [2]. Similar to other members of the NR superfamily, they contain both DNA and ligand-binding domains and work as obligate het- erodimers with retinoid X receptors (RXRs). As a general rule, regulation of ligand-dependent NRs can occur at the level of their expression and their activity, either through ligand availability or post-translational regulations. The latter, although beyond the scope of the present review, is increasingly being recognized as an essential component of PPAR and LXR functionality. Thus, for instance, mod- ifcations via phosphorylation, ubiquitination, and most recently the apparent PPAR -specifc SUMOylation, are emerging as ultimate determinants of these NRs’ ability to transactivate their target genes by affecting their inter- action with other co-factors as well as their stability [3,4]. Regulation of PPAR and LXR activity in the context of different biologic processes and cellular contexts has been the subject of excellent and comprehensive reviews. The purpose of this review is to summarize recent advances in our understanding of the transcriptional control of PPARs and LXRs and to describe the current knowledge on the molecular interplay between them to regulate key meta- bolic and physiologic events, as well as on the prevention of dyslipidemic disorders and cardiovascular diseases. PPARs and LXRs in Infammation and Atherosclerosis PPAR and LXR receptors, through different contributions, play an important role in lipid and glucose homeostasis and are key potential targets for therapeutic intervention to reduce the incidence of metabolic syndrome, which