| Structural highlights
Function
PPARD_HUMAN Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.[1] [2]
Publication Abstract from PubMed
Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARalpha (fibrates) and PPARgamma (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARdelta agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARalpha/delta/gamma share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARdelta/gamma when used as anti-NAFLD drugs. Therefore, this study examined their PPARalpha/delta/gamma selectivity using three independent assays-a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARdelta-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARdelta/gamma-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARalpha-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARdelta/gamma-bezafibrate, PPARgamma-fenofibric acid, and PPARdelta/gamma-pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.
Functional and Structural Insights into Human PPARalpha/delta/gamma Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.,Honda A, Kamata S, Akahane M, Machida Y, Uchii K, Shiiyama Y, Habu Y, Miyawaki S, Kaneko C, Oyama T, Ishii I Int J Mol Sci. 2022 Apr 25;23(9). pii: ijms23094726. doi: 10.3390/ijms23094726. PMID:35563117[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol. 1992 Oct;6(10):1634-41. PMID:1333051 doi:http://dx.doi.org/10.1210/mend.6.10.1333051
- ↑ van der Veen JN, Kruit JK, Havinga R, Baller JF, Chimini G, Lestavel S, Staels B, Groot PH, Groen AK, Kuipers F. Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1. J Lipid Res. 2005 Mar;46(3):526-34. Epub 2004 Dec 16. PMID:15604518 doi:http://dx.doi.org/10.1194/jlr.M400400-JLR200
- ↑ Honda A, Kamata S, Akahane M, Machida Y, Uchii K, Shiiyama Y, Habu Y, Miyawaki S, Kaneko C, Oyama T, Ishii I. Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate. Int J Mol Sci. 2022 Apr 25;23(9):4726. PMID:35563117 doi:10.3390/ijms23094726
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