Current Clinical Trial Status and Future Prospects of PPAR-Targeted Drugs for Treating Nonalcoholic Fatty Liver Disease

Biomolecules, Journal Year: 2023, Volume and Issue: 13(8), P. 1264 - 1264

Published: Aug. 18, 2023

The number of patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is increasing globally and raising serious concerns regarding the medical economic burden incurred for their treatment. progression NASH to more severe conditions such as cirrhosis hepatocellular carcinoma requires transplantation avoid death. Therefore, therapeutic intervention required in stage, although no drugs are currently available this. Several anti-NASH candidate have been developed that enable treatment via modulation distinct signaling cascades include a series targeting peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) considered be attractive because they can regulate both systemic lipid metabolism inflammation. Multiple PPAR dual/pan agonists but only few them evaluated clinical trials NAFLD/NASH. Herein, we review current trial status future prospects PPAR-targeted treating In addition, summarize our recent findings on binding modes potencies/efficacies several estimate potentials against NASH. Considering development numerous has abandoned side effects, also propose repositioning already approved, safety-proven

Language: Английский

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Peroxisome proliferator-activated receptors: A key link between lipid metabolism and cancer progression

Clinical Nutrition, Journal Year: 2023, Volume and Issue: 43(2), P. 332 - 345

Published: Dec. 9, 2023

Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling cellular function. One key hallmarks cancer is reprogramming metabolic pathways, especially abnormal lipid metabolism. Alterations uptake, desaturation, de novo lipogenesis, droplets, fatty acid oxidation cells all contribute to cell survival a changing microenvironment by regulating feedforward oncogenic signals, functions, oxidative other stresses, immune responses, or intercellular communication. Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated acids act core sensors involved regulation homeostasis fate. In addition whole-body energy physiological states, PPARs role metabolism cancer, which receiving increasing research attention, fundamental molecular mechanisms therapies targeting PPARs. this review, we discuss how alter patterns regulate promote their own progression through Finally, potential therapeutic strategies based on recent studies from last five years.

Language: Английский

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Pharmacological Utility of PPAR Modulation for Angiogenesis in Cardiovascular Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2345 - 2345

Published: Jan. 25, 2023

Peroxisome proliferator activated receptors, including PPARα, PPARβ/δ, and PPARγ, are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They play important roles in glucose lipid metabolism also supposed reduce inflammation atherosclerosis. All PPARs involved angiogenesis, a process critically cardiovascular pathology. Synthetic specific agonists exist for all PPARs. PPARα (fibrates) used treat dyslipidemia by decreasing triglyceride increasing high-density lipoprotein (HDL) levels. PPARγ (thiazolidinediones) Type 2 diabetes mellitus improving insulin sensitivity. PPARα/γ (dual) both pathological conditions at once. In contrast, PPARβ/δ not clinical use. Although activators of were initially considered have favorable effects on risk disease, their safety is controversial. Here, we discuss implications vascular biology regarding cardiac pathology focus outcomes studies evaluating benefits diseases.

Language: Английский

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Functional and Structural Insights into the Human PPARα/δ/γ Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor

Antioxidants, Journal Year: 2023, Volume and Issue: 12(8), P. 1523 - 1523

Published: July 29, 2023

No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual under investigation in clinical trials NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed obtain functional structural insights into potency, efficacy, selectivity against PPARα/δ/γ three current past anti-NASH investigational drugs: lanifibranor, seladelpar, elafibranor. Ligand activities were evaluated by assays detect different facets PPAR activation: transactivation assay, coactivator recruitment thermal stability assay. Seven high-resolution cocrystal structures (namely, those PPARα/δ/γ-ligand-binding domain (LBD)-lanifibranor, PPARα/δ/γ-LBD-seladelpar, PPARα-LBD-elafibranor) obtained through X-ray diffraction analyses, six which represent first deposit Protein Data Bank. Lanifibranor found bind regions pockets activated all with potencies efficacies assays. In contrast, induced (not stability) subtypes, but PPARδ/γ-LBD-elafibranor cocrystals not obtained. These results illustrate highly variable activation profiles binding modes these ligands define their pharmacological actions.

Language: Английский

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Deciphering the molecular pathways of saroglitazar: A dual PPAR α/γ agonist for managing metabolic NAFLD

Metabolism, Journal Year: 2024, Volume and Issue: 155, P. 155912 - 155912

Published: April 11, 2024

Language: Английский

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