The PPAR<i>Ω</i>Pocket: Renewed Opportunities for Drug Development

Kaupang, Åsmund; Hansen, Trond Vidar

doi:10.1155/2020/9657380

Cited by 10 publications

(8 citation statements)

References 248 publications

(458 reference statements)

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“…As a phosphoprotein, PPARα can also be activated through post-translational modification. The phosphorylation sites in PPARα include Ser12, Ser21, Ser179, and Ser230 ( 83 – 87 ). The increased transactivation of PPARα may occur via decreased co-repressor interaction, such as NCoR, or increased interaction with co-activators, such as Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) ( 88 ).…”

Section: Peroxisome Proliferator-activated Receptors (Ppars) Regulationmentioning

confidence: 99%

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

Xiao-ping

Zheng²,

Zhang³

et al. 2022

Front. Nutr.

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The consumption of phytochemicals, bioactive compounds in fruits and vegetables, has been demonstrated to ameliorate obesity and related metabolic symptoms by regulating specific metabolic pathways. This review summarizes the progress made in our understanding of the potential of phytochemicals as metabolic signals: we discuss herein selected molecular mechanisms which are involved in the occurrence of obesity that may be regulated by phytochemicals. The focus of our review highlights the regulation of transcription factors toll like receptor 4 (TLR4), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the peroxisome proliferator-activated receptors (PPARs), fat mass and obesity-associated protein (FTO) and regulation of microRNAs (miRNA). In this review, the effect of phytochemicals on signaling pathways involved in obesity were discussed on the basis of their chemical structure, suggesting molecular mechanisms for how phytochemicals may impact these signaling pathways. For example, compounds with an isothiocyanate group or an α, β-unsaturated carbonyl group may interact with the TLR4 signaling pathway. Regarding Nrf2, we examine compounds possessing an α, β-unsaturated carbonyl group which binds covalently with the cysteine thiols of Keap1. Additionally, phytochemical activation of PPARs, FTO and miRNAs were summarized. This information may be of value to better understand how specific phytochemicals interact with specific signaling pathways and help guide the development of new drugs to combat obesity and related metabolic diseases.

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Section: Peroxisome Proliferator-activated Receptors (Ppars) Regulationmentioning

confidence: 99%

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

Xiao-ping

Zheng²,

Zhang³

et al. 2022

Front. Nutr.

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“…As is known to all, PPAR γ demonstrated significant functions in the tissue protection and repair [ 22 – 24 ]. And advances in PPAR ligands and agonists renew opportunities for drug development [ 25 ]. Here, in our present study, we found that the activation of PPAR γ could confer hepatoprotective effects against hepatic IR injury and also investigated the therapeutic potential of PPAR γ agonists for the protection of hepatic injury.…”

Section: Discussionmentioning

confidence: 99%

PPARγ Plays an Important Role in Acute Hepatic Ischemia-Reperfusion Injury via AMPK/mTOR Pathway

Cheng

et al. 2021

PPAR Research

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Background. Hepatic ischemia-reperfusion (IR) injury is one of the severe complications associated with liver surgery and leads to liver dysfunction. PPARγ is always linked with various physiologic pathways, and it can alleviate liver damage in IR injury. Aim. In this study, we explored the potential mechanism of PPARγ in the pathogenesis of hepatic IR injury by mice model. Methods. After treated with si-PPARγ or rosiglitazone, mice were subjected to hepatic ischemia-reperfusion. Liver tissue and blood samples were collected to evaluate liver injury and detected relative mRNA and protein expressions. Results. The expression of PPARγ was increased after reperfusion. And the alleviation of PPARγ aggravated the liver damage in IR; at the same time, upregulation of the expression of PPARγ released the liver damage. And these effects of PPARγ in IR were related to the AMPK/mTOR/autophagy signaling pathway. Conclusion. PPARγ plays an important role in hepatic IR injury at least partly via the AMPK/mTOR/autophagy pathway.

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“…12,15−17 Drugs developed with the aid of these standard screens remain first-line therapies in human diseases such as cancer, 14 obesity, and diabetes. 18,19 Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor expressed mainly in the liver, 20−24 pancreas, 20,25,26 and gut 27−32 of adult mammals. A wide variety of chemical, genetic, and physiological studies have provided preclinical evidence that LRH-1 is a drug target with a high potential therapeutic value in type 2 diabetes, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis, 33−35 as well as pancreatic cancer and colorectal cancer, 8,25,36,37 all diseases with substantial unmet clinical need.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This standard model of nuclear receptor regulation has been validated in many receptors through structural and functional studies − and represents a rigorously tested, well-accepted regulatory model for this group of transcription factors. Based on this standard model, high-throughput compound screens have demonstrated outstanding effectiveness. − These screens monitor the physical interaction between a nuclear receptor LBD and an LXXLL-motif containing peptide from biologically relevant transcriptional coregulators. ,− Drugs developed with the aid of these standard screens remain first-line therapies in human diseases such as cancer, obesity, and diabetes. , …”

Section: Introductionmentioning

confidence: 99%

New High-Throughput Screen Discovers Novel Ligands of Full-Length Nuclear Receptor LRH-1

et al. 2023

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Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is a lipid-regulated transcription factor and an important drug target for several liver diseases. Advances toward LRH-1 therapeutics have been driven recently by structural biology, with fewer contributions from compound screening. Standard LRH-1 screens detect compound-induced interaction between LRH-1 and a transcriptional coregulator peptide, an approach that excludes compounds that regulate LRH-1 through alternative mechanisms. Here, we developed a FRET-based LRH-1 screen that simply detects compound binding to LRH-1, applying it to discover 58 new compounds that bind the canonical ligand-binding site in LRH-1 (2.5% hit rate), also supported by computational docking. Four independent functional screens identified 15 of these 58 compounds to also regulate LRH-1 function in vitro or in living cells. Although one of these 15 compounds, abamectin, directly binds LRH-1 and regulates full-length LRH-1 in cells, abamectin failed to regulate the isolated ligand-binding domain in standard coregulator peptide recruitment assays using PGC1α, DAX-1, or SHP. Abamectin treatment of human liver HepG2 cells selectively regulated endogenous LRH-1 ChIP-seq target genes and pathways associated with known LRH-1 functions in bile acid and cholesterol metabolism. Thus, the screen reported here can discover compounds not likely to have been identified in standard LRH-1 compound screens but which bind and regulate full-length LRH-1 in cells.

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The PPARΩPocket: Renewed Opportunities for Drug Development

Cited by 10 publications

References 248 publications

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

PPARγ Plays an Important Role in Acute Hepatic Ischemia-Reperfusion Injury via AMPK/mTOR Pathway

New High-Throughput Screen Discovers Novel Ligands of Full-Length Nuclear Receptor LRH-1

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