MicroRNAs-Dependent Regulation of PPARs in Metabolic Diseases and Cancers

Hindawi PPAR Research Volume 2017, Article ID 7058424, 19 pages https://doi.org/10.1155/2017/7058424 Review Article MicroRNAs-Dependent Regulation of PPARs in Metabolic Diseases and Cancers Dorothea Portius, Cyril Sobolewski, and Michelangelo Foti Department of Cell Physiology and Metabolism and Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland Correspondence should be addressed to Michelangelo Foti; Received 24 August 2016; Accepted 5 December 2016; Published 12 January 2017 Academic Editor: Valeria Amodeo Copyright © 2017 Dorothea Portius et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs’ expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed. 1. Introduction Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors involved in various biological functions but with a prominent role in metabolic homeostasis of carbohydrates and lipids [1]. The three PPAR isoforms, PPAR𝛼 (NR1C1), PPAR𝛽/𝛿 (NR1C2), and PPAR𝛾 (NR1C3), share 60% to 80% of structural homology [2, 3] and exhibit a distinct tissue expression pattern but can exert similar or different physiological functions [3]. In the canonical model, PPARs are activated in the cytoplasm by specific ligands [1–6] and then translocate into the nucleus, where they form a complex predominantly with the nuclear receptor Retinoid-X-Receptor (RXR), to transactivate gene expression by binding to PPAR response elements (PPREs) on gene promoters [6, 7]. In contrast, noncanonical PPAR activity suppresses gene transcription through direct protein-protein interactions with other transcription factors, for example, the nuclear factor-kB (NFkB) or activated protein-1 (AP-1) [1, 3]. PPARs activity is also tightly dependent on the binding of other cofactors such as PGC1𝛼 (peroxisome proliferatoractivated receptor coactivator-1𝛼) and p300 or CREB binding protein—or on the contrary on the binding of corepressor proteins, for example, NCOR (nuclear receptor corepressor) or SMRT (silencing mediator for retinoid and thyroid hormone receptor), which hamper PPARs interactions with PPRE [3]. Through complex regulatory mechanisms, PPARs exert a tight control on energy homeostasis by modulating the expression of key genes involved in lipid metabolism [5, 6], adipocytes differentiation [5], and carbohydrate metabolism [5, 6]. The implication of PPARs in inflammatory processes and specific cancers is further suggested by recent studies (reviewed in [3, 8, 9]). These key and pleiotropic roles of PPARs in cellular processes have led to the development of pharmacologic agonists, for example, thiazolidinediones and fibrates [10, 11], to treat metabolic disorders or other diseases such as atherosclerosis [2, 5, 12]. However, long-term treatment with PPARs agonists triggers uncontrolled side effects in patients (e.g., oedema, weight gain, heart failure, and bone fractures) and in some cases they may even promote tumorigenesis [6, 8, 13]. Alternative therapeutic options to control distinct PPARs activities in specific tissues are therefore desirable but require that we deepen our understanding of the molecular mechanisms controlling PPARs expression/activity in diseases. 2 Recently, a wealth of studies has suggested that epigenetic mechanisms, for example, DNA methylation, histone modifications, or small noncoding RNA (i.e., microRNAs), importantly affect physiological or pathological mechanisms involved in a wide variety of diseases and cancers. In the case of PPARs, methylation of their promoters [14, 15], or histone acetylation [16], has been reported to affect PPARs expression and physiological processes under their control. More recently, other epigenetic alterations, in particular those leading to abnormal microRNAs (miRNAs) expression, have also been implicated in the regulation of PPARs expression or activity [17]. Indeed several miRNAs were reported to either directly target PPARs mRNA or to indirectly affect their expression/activities by targeting PPARs-associated cofactors and repressors, thus providing a further level of complexity in these regulatory mechanisms [18–20]. In this review, we discuss the current knowledge about miRNAs-dependent regulation of PPARs and their cofactors in physiological and pathological processes. Most of available studies dealing with this topic are restrained to metabolic diseases (e.g., diabetes, fatty liver diseases, and cardiovascular diseases) and associated cancers (e.g., liver cancers) in tissues where the role of PPARs is well characterized (e.g., liver, adipose tissue, muscles, and heart). Other rare studies investigating PPARs regulation by miRNAs in different tissues (e.g., bone marrow, neurons, and cartilage) or type of cancers (e.g., neuroblastoma, prostate cancer), unrelated to metabolic disorders, are also considered. Finally, the reciprocal regulation of specific miRNAs by PPARs, as well as potential miRNAbased pharmacological approaches to therapeutically modulate PPARs expression and/or activity, was also examined. 2. miRNAs MicroRNAs (miRNAs) are endogenous small noncoding RNAs of approximately 16–22 nucleotides, which bind to complementary sequences (seed sequences) in the 3󸀠 UTR of target mRNAs and mediate either their decay or translation inhibition [21, 22]. miRNAs are encoded within intronic, intergenic regions or in polycistronic clusters [19, 23], and their biogenesis starts with a RNA polymerase II-dependent transcription of a primary transcript (pri-miRNA), which is then maturated by a nuclear microprocessor complex (RNase III Drosha and its mammalian double-stranded RNAbinding partner DGCR8). This leads to the release of a pre-miRNA, which is then exported into the cytoplasm by Exportin-5, where the RNase III Dicer1, together with its binding partner TARP2 (T-cell receptor gamma-chain constant region), removes the pre-miRNA hairpin loop and gene (...truncated)