PPAR Modulation Through Posttranslational Modification Control

Videira, Natália Bernardi; Dias, Marieli M. G.; Terra, Maiara Ferreira; Oliveira, Vinícius Martins de; García‐Arévalo, Marta; Avelino, Thayná Mendonça; Torres, Felipe Rafael; Batista, Fernanda Aparecida Heleno; Figueira, Ana Carolina Migliorini

doi:10.1007/978-3-030-78315-0_21

Cited by 5 publications

(1 citation statement)

References 364 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, we found that high glucose levels induced mir27-a expression, which downregulated PPARγ gene expression [ 61 ]. Contrasting with the lower mRNA levels, our results show that PPARγ S273A in the HFD-treated KI animals group presented increased protein content, suggesting that phosphorylation at S273 may regulate PPARγ levels by post-transcriptional mechanisms, as ubiquitination [ 62 , 63 , 64 ]. In fact, it is known that PPARγ is ubiquitinated by MKRN1 and Siah2 E3 ubiquitin ligases, which target it to proteasomal degradation in adipocytes [ 65 , 66 ].…”

Section: Discussionmentioning

confidence: 63%

Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

et al. 2023

View full text Add to dashboard Cite

Since the removal of thiazolidinediones (TZDs) from the market, researchers have been exploring alternative anti-diabetic drugs that target PPARγ without causing adverse effects while promoting insulin sensitization by blocking serine 273 phosphorylation (Ser273 or S273). Nonetheless, the underlying mechanisms of the relationship between insulin resistance and S273 phosphorylation are still largely unknown, except for the involvement of growth differentiation factor (GDF3) regulation in the process. To further investigate potential pathways, we generated a whole organism knockin mouse line with a single S273A mutation (KI) that blocks the occurrence of its phosphorylation. Our observations of KI mice on different diets and feeding schedules revealed that they were hyperglycemic, hypoinsulinemic, presented more body fat at weaning, and presented an altered plasma and hepatic lipid profile, distinctive liver morphology and gene expression. These results suggest that total blockage of S273 phosphorylation may have unforeseen effects that, in addition to promoting insulin sensitivity, could lead to metabolic disturbances, particularly in the liver. Therefore, our findings demonstrate both the beneficial and detrimental effects of PPAR S273 phosphorylation and suggest selective modulation of this post translational modification is a viable strategy to treat type 2 diabetes.

show abstract

Section: Discussionmentioning

confidence: 63%

Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

et al. 2023

View full text Add to dashboard Cite

show abstract

Design, synthesis and biological evaluation of cajanonic acid A analogues as potent PPAR γ antagonists

Shi

Ban³

et al. 2023

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

Interactions governing transcriptional activity of nuclear receptors

Khan

Okafor

2022

Biochemical Society Transactions

View full text Add to dashboard Cite

The key players in transcriptional regulation are transcription factors (TFs), proteins that bind specific DNA sequences. Several mechanisms exist to turn TFs ‘on’ and ‘off’, including ligand binding which induces conformational changes within TFs, subsequently influencing multiple inter- and intramolecular interactions to drive transcriptional responses. Nuclear receptors are a specific family of ligand-regulated TFs whose activity relies on interactions with DNA, coregulator proteins and other receptors. These multidomain proteins also undergo interdomain interactions on multiple levels, further modulating transcriptional outputs. Cooperation between these distinct interactions is critical for appropriate transcription and remains an intense area of investigation. In this review, we report and summarize recent findings that continue to advance our mechanistic understanding of how interactions between nuclear receptors and diverse partners influence transcription.

show abstract

PPAR Modulation Through Posttranslational Modification Control

Cited by 5 publications

References 364 publications

Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

Design, synthesis and biological evaluation of cajanonic acid A analogues as potent PPAR γ antagonists

Interactions governing transcriptional activity of nuclear receptors

Contact Info

Product

Resources

About