The Potential Roles of Post-Translational Modifications of PPARγ in Treating Diabetes

Abstract

The number of patients with type 2 diabetes mellitus (T2DM), which is mainly characterized by insulin resistance and insulin secretion deficiency, has been soaring in recent years. Accompanied by many other metabolic syndromes, such as cardiovascular diseases, T2DM represents a big challenge to public health and economic development. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear receptor that is critical in regulating glucose and lipid metabolism, has been developed as a powerful drug target for T2DM, such as thiazolidinediones (TZDs). Despite thiazolidinediones (TZDs), a class of PPARγ agonists, having been proven to be potent insulin sensitizers, their use is restricted in the treatment of diabetes for their adverse effects. Post-translational modifications (PTMs) have shed light on the selective activation of PPARγ, which shows great potential to circumvent TZDs' side effects while maintaining insulin sensitization. In this review, we will focus on the potential effects of PTMs of PPARγ on treating T2DM in terms of phosphorylation, acetylation, ubiquitination, SUMOylation, O-GlcNAcylation, and S-nitrosylation. A better understanding of PTMs of PPARγ will help to design a new generation of safer compounds targeting PPARγ to treat type 2 diabetes.

Keywords: PPARγ; diabetes; post-translational modifications; thiazolidinediones.

Figure 1

Structural characteristics and species conservation of PPARγ. Schematic diagram of the PPARγ protein structure includes the activation function 1 and 2 domains (AF1 and AF2), DNA binding domain (DBD), and ligand-binding domain (LBD).

Figure 2

Specific distribution of partial modification sites in the LBD region of PPARγ. (a) Modification sites in the LBD region of PPARγ. This structure is a ligand-free structure of human PPARγ LBD. (PDB DOI: 10.2210/pdb6L8B/pdb. NDB: 6L8B) (Accessed on 16 September 2020. www.rcsb.org). (b) Schematic diagram of experimental procedures for the detection of Phosphorylated PPARγ. The modification sites for PPARγ phosphorylation are shown in the circle: Ser273. In addition to the site Ser273, the other site where phosphorylation of PPARγ occurs is Thr78, which is located within AF1. (c,d) Schematic diagram of experimental procedures for the detection of Deacetylated PPARγ. The modification sites for PPARγ phosphorylation are shown in the circle: Lys268, Lys293. (e) Schematic diagram of experimental procedures for the detection of Ubiquitinated PPARγ. The modification sites for PPARγ ubiquitination are shown in the circle: Lys462.