The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis.

Pengfei Xu,Jing Wang,Yonggong Zhai

doi:10.3390/ijms19041260

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.

Highlights

Obesity is a lipid metabolic disturbance that has been growing across the world for nearly half a century
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 acid transport protein (FATP), carnitine palmitoyltransferase I (CPT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [20,22]
We reported that activation of Constitutive androstane receptor (CAR) inhibited lipogenesis by suppressing liver X receptors (LXRs) ligand-responded recruitment of LXR to the LXR response element (LXRE) and the expression of LXR target genes, whereas activation of LXR inhibited the CAR ligand-induced recruitment of CAR to Cyp2b10 [74]

Summary

Introduction

Obesity is a lipid metabolic disturbance that has been growing across the world for nearly half a century. Sci. 2018, 19, 1260 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]. 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 acid transport protein (FATP), carnitine palmitoyltransferase I (CPT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [20,22]. AAlltthhoouugghh CCAARR iiss aa ppootteennttiiaall tthheerraappeeuuttiicc ttaarrggeett ffoorr lliippiidd mmeettaabboolliicc ddiisseeaassee,, ssoommee bbaarrrriieerrss eexxiisstt ffoorr tthhee cclliinniiccaall uussee ooff iittss aaggoonniissttss:: tthheerree aarree ccoonncceerrnnss aarroouunndd hheeppaattiicc eennllaarrggeemmeenntt aanndd ccaarrcciinnooggeenneessiiss. Better understanding of these mechanistic properties might help us overcome these barriers in the future

Oxysterol Sensor LXRs

Cross-Talk of PPARS and LXRS in Atherosclerosis

Conclusions