PPARα and NCOR/SMRT corepressor network in liver metabolic regulation

Peroxisome proliferator-activated receptor alpha (PPARα, NR1C1) belongs to a large family of ligand-dependent nuclear receptors (NRs). It is one of the best studied NRs which controls the lipid metabolism (mainly fatty acid oxidation) and inflammation, and has been a promising target for treating metabolic disorders such as fatty liver and cardiometabolic diseases. The function of PPARα relies on its interaction with various coregulators upon different stimulating contexts, and, thereby, activates or represses its transcription targets in a gene-selective manner. Understanding the transcription factor and coregulator network underlying the PPARα regulation is prerequisite to decipher its gene- and context-selectivity for designing better therapeutic ligands. In this review, we will summarize current knowledge of PPARα coregulator network, with major focus on a relatively well-studied corepressor complex containing core subunits of nuclear receptor corepressor (NCOR or NCOR1), silencing mediator of retinoic acid and thyroid hormone receptor (SMRT or NCOR2), G-protein suppressor 2 (GPS2), transducin β-like protein 1 (TBL1 or TBL1X), TBL-related 1 (TBLR1 or TBL1XR1), and the catalytic core of histone deacetylase 3 (HDAC3). We will mainly review the molecular events of the complex and sub-complexes in controlling the liver metabolism. We will also discuss the potential perturbation of the subunit expression in human livers during liver metabolic disorder progression which potentially defines the patient disease susceptibility and drug responses.