Functional Regulation of PPARs through Post-Translational Modifications

Abstract

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and they are essential regulators of cell differentiation, tissue development, and energy metabolism. Given their central roles in sensing the cellular metabolic state and controlling metabolic homeostasis, PPARs became important targets of drug development for the management of metabolic disorders. The function of PPARs is mainly regulated through ligand binding, which induces structural changes, further affecting the interactions with co-activators or co-repressors to stimulate or inhibit their functions. In addition, PPAR functions are also regulated by various Post-translational modifications (PTMs). These PTMs include phosphorylation, SUMOylation, ubiquitination, acetylation, and O-GlcNAcylation, which are found at numerous modification sites. The addition of these PTMs has a wide spectrum of consequences on protein stability, transactivation function, and co-factor interaction. Moreover, certain PTMs in PPAR proteins have been associated with the status of metabolic diseases. In this review, we summarize the PTMs found on the three PPAR isoforms PPARα, PPARβ/δ, and PPARγ, and their corresponding modifying enzymes. We also discuss the functional roles of these PTMs in regulating metabolic homeostasis and provide a perspective for future research in this intriguing field.

Notch signaling increases PPARγ protein stability and enhances lipid uptake through AKT in IL‐4‐stimulated THP‐1 and primary human macrophages

“…Therefore, Notch signaling did not regulate PPARG transcription or its mRNA stability. Previous reports found that the stability of PPARγ was regulated by proteasomal degradation [17,34]. We then asked whether Notch signaling regulates the stability of PPARγ by this mechanism.…”

“…PPARγ degradation is regulated mainly by proteasomal degradation, which is mediated through PPARγ E3 ligases [17]. MAPK/ERK‐kinase 1/2 (MEK1/2) activation directly interacts with PPARγ in the nucleus and supports its export to function in a transcriptional activity‐independent manner or its degradation by the proteasome in the cytoplasm [18].…”

The Lipid Handling Capacity of Subcutaneous Fat Is Programmed by mTORC2 during Development

“…How might mTORC2 regulate PPARγ activity? One possibility is that a PPARγ post-translational modification(s), such as phosphorylation, acetylation, SUMOylation, or O-GlcNAcylation, could be sensitive to mTORC2 signaling ( Brunmeir and Xu 2018 ; Floyd and Stephens, 2004 ; Jennewein et al, 2008 ; Ji et al, 2012 ; Ohshima et al, 2004 ; Pascual et al, 2005 ). For example, phosphorylation of PPARγ increases or decreases its activity depending on the sites and the upstream regulators ( Choi et al, 2014 , 2010 ; Compe et al, 2005 ; Helenius et al, 2009 ; Hu et al, 1996 ; Iankova et al, 2006 ; Adams et al, 1997 ).…”

Gegen Qinlian Decoction Coordinately Regulates PPARγ and PPARα to Improve Glucose and Lipid Homeostasis in Diabetic Rats and Insulin Resistance 3T3-L1 Adipocytes

“…Additionally, GQD decreased the phosphorylation level of ERK1/2 and CDK5 to elevate PPARg and PPARa activities in IR-3T3-L1 adipocytes. Increases in phosphorylation level of p38MAPK and SIRT1 expression may be attributed to inhibit PPARg adipogenesis activity and activate PPARa activity through differentiated recruitment of cofactors including PGC-1a for mitochondrial energy homeostasis ( Figure 9C) (Barger et al, 2001;Kim et al, 2013;Banks et al, 2015;Brunmeir and Xu, 2018). In this study, PGC-1a expression was elevated in WAT of diabetic rats or IR-3T3-L1 with GQD treatment, which it may be partially through deacetylation of PGC-1a by SIRT and phophorylation of PGC-1a to increase its protein stability for coactivation of PPARa and/or PPARg transcription (Miller et al, 2019).…”