International Journal of Molecular Sciences Review The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis Pengfei Xu 1,2, Yonggong Zhai 1,2,* and Jing Wang 3,* 1 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China; [email protected] 2 Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China 3 Department of Biology Science and Technology, Baotou Teacher’s College, Baotou 014030, China * Correspondence: [email protected] (Y.Z.); [email protected] (J.W.); Tel.: +86-10-5880-6656 (Y.Z.); +86-186-482-6849 (J.W.) Received: 26 March 2018; Accepted: 19 April 2018; Published: 23 April 2018 Abstract: The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease. Constitutive androstane receptor (CAR) and liver X receptors (LXRs) were also reported as potential therapeutic targets for the treatment of obesity and atherosclerosis, respectively. Further clarification of the internal relationships between these three lipid metabolic nuclear receptors is necessary to enable drug discovery. In this review, we mainly summarized the cross-talk of PPARs-CAR in obesity and PPARs-LXRs in atherosclerosis. Keywords: PPAR; CAR; LXR; obesity; atherosclerosis 1. Introduction Obesity is a lipid metabolic disturbance that has been growing across the world for nearly half a century. It is a global human health concern. In 2016, more than 1.9 billion adults (≥18 years old) were overweight and, of these, over 650 million were obese. Furthermore, 340 million children and adolescents (5–18 years old) and 41 million children (≤5 years old) were overweight or obese [1,2]. The body mass index (BMI), defined as a person’s weight in kilograms divided by the square of their height in meters, is a simple index used to classify overweight and obesity in adults. Obesity is associated with various metabolic disorders and cardiovascular diseases. A high BMI is considered to be an indicator of high body fatness that may lead to a high risk of cardiometabolic syndrome and atherosclerotic vascular disease [3–5]. Atherosclerosis, also known as arteriosclerosis, hardening of the arteries, is a disease in which fatty plaque deposits build up inside the arteries, narrowing them, leading to some serious problems, including coronary artery disease, stroke, or even death [6]. Obesity and atherosclerosis are common chronic lipid metabolic disorder diseases. The treatment and prevention of obesity and atherosclerosis are both major challenges, and studying this problem can help us live longer, healthier lives. Nuclear receptors (NRs), a class of ligand-activated transcriptional factors, play significant roles in metabolic homeostasis. It is well known that there are 48 and 49 NR genes in humans (Homo sapiens) and mice (Mus musculus), respectively [7,8]. Most of the NRs contain six functional domains, such as the variable N-terminal regulatory domain (A–B), the conserved DNA-binding domain (DBD) (C), the variable hinge region (D), the conserved ligand binding domain (LBD) (E), and the variable Int. J. Mol. Sci. 2018, 19, 1260; doi:10.3390/ijms19041260 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, 1260 2 of 17 C-terminalInt. J. Mol. Sci. domain 2018, 19, (F)x FOR (Figure PEER REVIEW1a) [ 7, 9 ]. The classical function of NRs is to transcriptionally regulate2 of 17 the expression of cognate target genes through the recruitment of coactivators or corepressors when ligandsexpression bind of to thecognate receptors target [10genes,11] (Figurethrough1 b).the Torecruitment perform theof coactivators transcriptional or corepressors activity, NRs when either ligands bind to the receptors [10,11] (Figure 1b). To perform the transcriptional activity, NRs either (1) act as monomers; (2) need to form dimeric complexes (homodimers); or (3) form complexes with (1) act as monomers; (2) need to form dimeric complexes (homodimers); or (3) form complexes with the retinoid X receptor (RXR) (heterodimers) and bind to the DNA in the cell nucleus [9]. Recently, the retinoid X receptor (RXR) (heterodimers) and bind to the DNA in the cell nucleus [9]. Recently, many studies have indicated the role of some NRs in the regulation of lipid metabolism. It has many studies have indicated the role of some NRs in the regulation of lipid metabolism. It has been been recognized that peroxisome proliferator-activated receptors (PPARs) act as fatty acid sensors, recognized that peroxisome proliferator-activated receptors (PPARs) act as fatty acid sensors, regulatingregulating the the multiple multiple pathwayspathways involvedinvolved in lipid lipid and and glucose glucose metabolism metabolism and and overall overall energy energy metabolismmetabolism [12 [12,13,13].]. Furthermore,Furthermore, thethe constitutive androstane androstane receptor receptor (CAR), (CAR), which which was was initially initially characterizedcharacterized as as a a xenosensor xenosensor thatthat controlscontrols xenobiotic responses, responses, has has been been recently recently identified identified as asa a therapeutictherapeutic target target for for obesity obesity andand itsits relatedrelated metabolic disorders disorders [14,15 [14,15], ],whereas whereas liver liver X Xreceptors receptors (LXRs)(LXRs) are are sterol sterol sensors sensors that that mainly mainly regulate regulate cholesterol, cholesterol, fatty fatty acid acid and and glucose glucose homeostasis, homeostasis, they they can inhibitcan inhibit atherosclerosis atherosclerosis development, development, but promote but promote lipogenesis lipogenesis in liver in liver [16]. [16]. In this In review,this review, we brieflywe summarizebriefly summarize the roles the of PPARs, roles of CARPPARs, and CAR LXRs and and LXRs their and ligands their ligands in the treatment in the treatment of metabolic of metabolic diseases, obesitydiseases, and obesity atherosclerosis, and atherosclerosis and discuss, and di thescuss cross-talk the cross of-talk PPARs-CAR of PPARs-CAR and and PPARs-LXRs PPARs-LXRs in lipidin metabolismlipid metabolism regulation. regulation. FigureFigure 1. 1.Schematic Schematic structure structure ofof NRsNRs (nuclear(nuclear receptors) and and model model of of NR NR signalling signalling.. (a) ( aGeneral) General domaindomain structure structure of of NRs; NRs; and and (b(b)) thethe mechanismmechanism of general general NR NR action. action. The The ligands ligands bind bind to tothe the LBD LBD (ligand-binding(ligand-binding domain) domain) ofof NRsNRs inin thethe cytoplasm,cytoplasm, and translocate translocate to to the the nucleus. nucleus. Then Then the the DBD DBD (DNA-binding(DNA-binding domain) domain) ofof NRsNRs bindbind toto thethe XRE (xenobiotic responsive responsive elements) elements) form forminging dimeric dimeric complexescomplexes with with RXR RXR and and the the recruitmentrecruitment of co-activatorsco-activators or or co co-repressors.-repressors. Finally, Finally, this this leads leads to tothe the transcriptiontranscription of of the the target target genes. genes. ThisThis model is is applied applied to to type type II II NRs, NRs, including including PPARs, PPARs, CAR, CAR, LXRs LXRs,, andand others. others. The The colorful colorful words words justjust matchmatch the corresponding colorful colorful shape. shape. The The dotted dotted arrows arrows mean mean differentdifferent ligands ligands can can recruit recruit coactivators coactivators oror corepressorscorepressors to form form dimers, dimers, respectively. respectively. 2. The Initial Characterization of PPAR, CAR, and LXR 2. The Initial Characterization of PPAR, CAR, and LXR 2.1.2.1. Fatty Fatty Acids Acids Sensor Sensor PPARs PPARs PPARs are molecular sensors of fatty acids and fatty acid derivatives and control energy PPARs are molecular sensors of fatty acids and fatty acid derivatives and control energy homeostasis (carbohydrate, lipid, and protein) [17]. There are three types of PPARs which have been homeostasis (carbohydrate, lipid, and protein) [17]. There are three types of PPARs which have identified: PPARα (NR1C1, encoded by PPARA), PPARβ/δ (NR1C2, encoded by PPARD), and Int. J. Mol. Sci. 2018, 19, 1260 3 of 17 been identified: PPARα (NR1C1, encoded by PPARA), PPARβ/δ (NR1C2, encoded by PPARD), and PPARγ (NR1C3, encoded by PPARG). They are all lipid sensors that transcriptionally regulate diverse aspects in response to nutritional inputs, and serving as effective therapeutic targets for some types of lipid metabolic syndrome, including obesity, atherosclerosis, dyslipidaemia, type 2 diabetes mellitus (T2DM), and nonalcoholic fatty liver disease (NAFLD) [12,18]. PPARα is highly active in liver, brown adipose tissue (BAT), kidney, heart, and muscle tissue [19], where it regulates the adaptive response to prolonged fasting by controlling the process of ketogenesis, fatty acid transport, fatty acid binding, fatty acid activation and mitochondrial fatty acid β-oxidation [20,21]. Genomic studies have indicated that PPARα, as a master regulator of lipid metabolism, has various target genes; the classical genes include acyl-CoA oxidase, thiolase, fatty