Novel intervention for alcohol-associated liver disease DOI

Fei-Qiong Gao,

Jiaqi Zhu,

Xudong Feng

et al.

World Journal of Gastroenterology, Journal Year: 2024, Volume and Issue: 30(39), P. 4308 - 4312

Published: Oct. 11, 2024

A recently published article in the World Journal of Gastroenterology clarified that elafibranor, a dual peroxisome proliferator activated receptor α/δ (PPARα/δ) agonist, reduced inflammation and fibrosis alcohol-associated liver disease (ALD). This letter aims to discuss findings presented article. ALD is global health problem, no effective drugs has been approved by Food Drug Administration cure it. Thus, finding targeted therapies great urgency. Herein, we focus on pathogenesis role PPARα/δ its development. Consistent with conclusion interest, think elafibranor may be promising therapeutic option for ALD, due pivotal involvement disease. However, treatment dose, timing, side effects need further investigated future studies.

Language: Английский

Competitive Ligand-Induced Recruitment of Coactivators to Specific PPARα/δ/γ Ligand-Binding Domains Revealed by Dual-Emission FRET and X-Ray Diffraction of Cocrystals DOI Creative Commons
S Kamata,

Akihiro Honda,

Sayaka Yashiro

et al.

Antioxidants, Journal Year: 2025, Volume and Issue: 14(4), P. 494 - 494

Published: April 20, 2025

Peroxisome proliferator-activated receptors (PPARs), composed of the α/δ/γ subtypes, are ligand-activated nuclear receptors/transcription factors that sense endogenous fatty acids or therapeutic drugs to regulate lipid/glucose metabolism and oxidative stress. PPAR forms a multiprotein complex with retinoid X receptor corepressor in an unliganded/inactive state, ligand binding induces replacement coactivator initiate transcription various genes, including metabolic antioxidant ones. We investigated processes by which is replaced two coactivators compete for PPARα/δ/γ-ligand-binding domains (LBDs) using single- dual-emission fluorescence resonance energy transfer (FRET) assays. Single-FRET revealed respective PPARα/δ/γ-selective agonists (pemafibrate, seladelpar, pioglitazone) induced dissociation peptides, NCoR1 NCoR2, from PPARα/δ/γ-LBDs recruitment CBP TRAP220. Meanwhile, dual-FRET demonstrated these simultaneous four CBP, TRAP220, PGC1α, SRC1, were competitively recruited different preferences upon activation. Furthermore, five newly obtained cocrystal structures X-ray diffraction, PPARα-LBDs–NCoR2/CBP/TRAP220/PGC1α PPARγ-LBD–NCoR2, co-analyzed those our previous studies. This illustrates bound same PPARα-LBD loci via their consensus LXXLL motifs liganded state; NCoR1/NCoR2 corepressors IXXXL sequences within LXXXIXXXL unliganded activation AF-2 helix 12 formation interfered created space coactivator. These PPARα/γ-related biochemical physicochemical findings highlight coregulator dynamics on limited loci.

Language: Английский

Citations

0
Alstonia scholaris (L.) R. Br. ameliorated diabetic nephropathy through PPAR-δ pathway DOI

Shi-Shi Qin,

Cai-Bo Tian,

Yan-Ling Qian

et al.

Journal of Ethnopharmacology, Journal Year: 2025, Volume and Issue: 348, P. 119839 - 119839

Published: April 26, 2025

Language: Английский

Citations

0
Retinoid X receptor heterodimers in hepatic function: structural insights and therapeutic potential DOI Creative Commons

Renjie Xu,

Linyue Zhang,

Hao Pan

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 16, 2024

Nuclear receptors (NRs) are key regulators of multiple physiological functions and pathological changes in the liver response to a variety extracellular signaling changes. Retinoid X receptor (RXR) is special member NRs, which not only responds cellular independently, but also regulates pathways by forming heterodimers with various other NR. Therefore, RXR widely involved hepatic glucose metabolism, lipid cholesterol metabolism bile acid homeostasis as well fibrosis. Specific activation particular dimers regulating processes may serve important pharmacological targets. So here we describe basic information structural features protein its heterodimers, focusing on role number imbalances liver, provide theoretical basis for promising drug target.

Language: Английский

Citations

1
Pemafibrate Induces a Low Level of PPARα Agonist-Stimulated mRNA Expression of ANGPTL4 in ARPE19 Cell DOI Creative Commons

Hiroshi Ohguro,

Nami Nishikiori, Tatsuya Sato

et al.

Bioengineering, Journal Year: 2024, Volume and Issue: 11(12), P. 1247 - 1247

Published: Dec. 9, 2024

To elucidate the unidentified roles of a selective peroxisome proliferator-activated receptor α (PPARα) agonist, pemafibrate (Pema), on pathogenesis retinal ischemic diseases (RID)s, pharmacological effects Pema pigment epithelium (RPE), which is involved in RID, were compared with non-fibrate PPARα agonist GW7647 (GW). For this purpose, human RPE cell line ARPE19 that was untreated (NT) or treated GW subjected to Seahorse cellular metabolic analysis and RNA sequencing analysis. Real-time function revealed actions essential functions cells substantially different between Pema-treated GW-treated cells. following differentially expressed genes (DEGs): (1) NT vs. cells, 37 upregulated 72 downregulated DEGs; (2) 32 54 (3) GW, 67 51 markedly DEGs. Gene ontology (GO) ingenuity pathway (IPA) showed several overlaps differences biological pathways estimated by DEGs presumably due common unspecific off-target each. further estimation, among pairs comparisons (NT Pema, GW) listed up. Angiopoietin-like 4 (ANGPTL4), has been shown cause deterioration only DEG identified as significantly all three comparisons, suggesting ANGPTL4 action but its levels lower than In qPCR analysis, such efficacy for upregulation mRNA expression confirmed, addition substantial HIF1α both agonists. However, GW-induced (Pema, no change; downregulated) upregulated; observed HepG2 hepatocyte line. The results study suggest agonists are organ-specific DR-worsening factor may minimize risk development RID.

Language: Английский

Citations

1
Tuning RXR Modulators for PGC1α Recruitment DOI
Felix Nawa, Minh Sai, Jan Vietor

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

The molecular activation mechanism of the nuclear retinoid X receptors (RXRs) crucially involves ligand-induced corepressor release and coactivator recruitment which mediate transcriptional repression or activation. ability RXR to bind diverse coactivators suggests that a coregulator-selective modulation by ligands may open an avenue tissue- gene-selective Here, we identified strong induction peroxisome proliferator-activated receptor γ 1α (PGC1α) binding synthetic agonist but not endogenous ligand 9-cis retinoic acid. Structure-guided diversification this lead resulted in set three structurally related agonists with different promote PGC1α cell-free cellular context. These results demonstrate selective coregulator can be achieved glues potentially new therapeutic opportunities targeting RXR-PGC1α interaction.

Language: Английский

Citations

0
Novel intervention for alcohol-associated liver disease DOI

Fei-Qiong Gao,

Jiaqi Zhu,

Xudong Feng

et al.

World Journal of Gastroenterology, Journal Year: 2024, Volume and Issue: 30(39), P. 4308 - 4312

Published: Oct. 11, 2024

A recently published article in the World Journal of Gastroenterology clarified that elafibranor, a dual peroxisome proliferator activated receptor α/δ (PPARα/δ) agonist, reduced inflammation and fibrosis alcohol-associated liver disease (ALD). This letter aims to discuss findings presented article. ALD is global health problem, no effective drugs has been approved by Food Drug Administration cure it. Thus, finding targeted therapies great urgency. Herein, we focus on pathogenesis role PPARα/δ its development. Consistent with conclusion interest, think elafibranor may be promising therapeutic option for ALD, due pivotal involvement disease. However, treatment dose, timing, side effects need further investigated future studies.

Language: Английский

Citations

0