Any alteration in PPAR genomic sequence, splicing pattern, or PTM is likely to cause major alterations in its function. In personalized medicine, such data becomes more significant in gene therapy design
Moataz Dowaidar
Abstract
Proliferator-activated gamma receptor (PPAR) is a paradigm of how numerous signaling networks converge on a single component whose activity is controlled by a sophisticated system of alternative splicing, post-translation alterations and coactivator and repressor interactions. The prevalence of several regulatory layers in PPAR signaling explains its time-and tissue-specific responses, suggesting that any change in the genomic sequence, pattern of splicing, or PTM is likely to produce large changes in its activity. Because the variety of PPARG genetic variants is so wide, from common SNPs to rare nucleotide variants or mutations, understanding if and how each variation impacts PPAR signaling is crucial to evaluating disease risk. Moreover, in the era of personalized medicine, such data has become more relevant in predicting the efficacy of TZD-based therapies, enabling the building of more robust decision trees to treat metabolic illnesses.Alternative splicing and post-translation changes were previously ignored PPAR biology components, according to several independent evidence lines. In this regard, the discovery of naturally occurring PPARG isoforms expressed in adipose tissue and having dominant-negative activity towards canonical receptors underlines the importance of paying special attention when designing a PPAR study, particularly for cells or tissues where it is highly expressed. Indeed, the absence of rigorous experimental design to discriminate between functional and non-functional isoforms is highly likely to result in misinterpretation of findings. It is harder to foresee or understand the effect of PPAR-modulating drugs in the absence of data on the expression of dominant-negative isoforms or their ratio vs. canonical isoforms, making any choice based on these results particularly harmful. Similarly, multiple independent experiments have demonstrated that endogenous (or exogenous) factors have a considerable influence on variations in PPAR protein and therefore activity. As a result, it is crucial to consider all these aspects in investigating PPAR, especially in a disease setting. Considering the various interwoven regulatory levels of PPAR activity, new insights into PPAR signaling in human pathophysiology might lead to novel ways to improve existing therapies for PPAR-related metabolic diseases.