ERRα as a Bridge Between Transcription and Function: Role in Liver Metabolism and Disease

Abstract

As transcriptional factors, nuclear receptors (NRs) function as major regulators of gene expression. In particular, dysregulation of NR activity has been shown to significantly alter metabolic homeostasis in various contexts leading to metabolic disorders and cancers. The orphan estrogen-related receptor (ERR) subfamily of NRs, comprised of ERRα, ERRβ, and ERRγ, for which a natural ligand has yet to be identified, are known as central regulators of energy metabolism. If AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) can be viewed as sensors of the metabolic needs of a cell and responding acutely via post-translational control of proteins, then the ERRs can be regarded as downstream effectors of metabolism via transcriptional regulation of genes for a long-term and sustained adaptive response. In this review, we will focus on recent findings centered on the transcriptional roles played by ERRα in hepatocytes. Modulation of ERRα activity in both in vitro and in vivo models via genetic or pharmacological manipulation coupled with chromatin-immunoprecipitation (ChIP)-on-chip and ChIP-sequencing (ChIP-seq) studies have been fundamental in delineating the direct roles of ERRα in the control of hepatic gene expression. These studies have identified crucial roles for ERRα in lipid and carbohydrate metabolism as well as in mitochondrial function under both physiological and pathological conditions. The regulation of ERRα expression and activity via ligand-independent modes of action including coregulator binding, post-translational modifications (PTMs) and control of protein stability will be discussed in the context that may serve as valuable tools to modulate ERRα function as new therapeutic avenues for the treatment of hepatic metabolic dysfunction and related diseases.

Keywords: diabetes; high-fat diet; inflammation; liver cancer; metabolism; non-alcoholic fatty liver disease; nuclear receptor.

Figure 1

Bioinformatics analysis of direct ERRα target genes in mouse liver. Word clouds representing significantly overrepresented GO cellular component terms (top, green), KEGG pathways (right, blue) and the top 50 canonical pathways from Ingenuity Pathway Analysis (IPA) (left, purple) from the list of ERRα target genes with DNA binding events observed within ±10 kb of their transcription start sites as identified by ChIP-seq analysis (23). The size of the significant terms is reflective of their associated p-values whereby the most significant terms having lower p-values are displayed in larger font size.

Figure 2

ERRα-regulated target genes and programs in liver cells. ERRα target genes (104) found transcriptionally regulated by ERRα in a positive (increased by ERRα, red) or negative (decreased by ERRα, blue) manner in hepatocytes from in vivo and in vitro studies involving genetic or pharmacological manipulation of ERRα activity are shown. Only ERRα-regulated genes having a high confidence for direct gene regulation by ERRα as determined by the presence of an ERRα-binding event within ±20 kb of the gene transcriptional start site were considered (22, 23). The genes, Sdhb, Sdhc, and Sdhd were associated to two biological programs. See also Table S1 for more information.

Figure 3

Current knowledge on the role of ERRα in liver physiology and pathology. Biological processes found either positively or negatively regulated by ERRα are shown. Under physiological conditions, ERRα can stimulate mitochondrial function and nutrient catabolism and repress de novo lipogenesis, gluconeogenesis and insulin signaling. Under pathological conditions, ERRα promotes the development of HFD-induced NAFLD on one hand and represses inflammation and protects from the development of rapamycin-induced NAFLD and liver cancer on the other.