Development of a Ligand Screening Tool Using Full-Length Human Peroxisome Proliferator-Activated Receptor-Expressing Cell Lines to Ameliorate Metabolic Syndrome

Abstract

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily and include three subtypes (PPARα, PPARδ, and PPARγ). They regulate gene expression in a ligand-dependent manner. PPARα plays an important role in lipid metabolism. PPARγ is involved in glucose metabolism and is a potential therapeutic target in Type 2 diabetes. PPARδ ligands are candidates for the treatment of metabolic disorders. Thus, the detection of PPAR ligands may facilitate the treatment of various diseases. In this study, to identify PPAR ligands, we engineered reporter cell lines that can be used to quantify PPARγ and PPARδ activity. We evaluated several known ligands using these reporter cell lines and confirmed that they are useful for PPAR ligand detection. Furthermore, we evaluated extracts of approximately 200 natural resources and found various extracts that enhance reporter gene activity. Finally, we identified a main alkaloid of the Evodia fruit, evodiamine, as a PPARγ activator using this screening tool. These results suggest that the established reporter cell lines may serve as a useful cell-based screening tool for finding PPAR ligands to ameliorate metabolic syndromes.

Chemical Screening of Nuclear Receptor Modulators

“…Tachibana et al described a reporter assay system that can be used to assess PPARγ (NR1C3) and PPARδ (NR1C2) activities. This assay system was used to evaluate approximately 200 natural resource extracts and PPARγ (NR1C3) activators, and identified the alkaloid evodiamine from Evodia fruit as a hit [ 107 ]. In such assays, it is often necessary to purify and identify the active ingredients from plant extracts.…”

On the Inhibitability of Natural Products Isolated from Tetradium ruticarpum towards Tyrosine Phosphatase 1B (PTP1B) and α-Glucosidase (3W37): An In Vitro and In Silico Study

“…Moreover, a major quinolone alkaloid compound, evodiamine, extracted from E. rutaecarpa reduced obesity and insulin resistance in obese/diabetic KK-Ay mice via signal [ 17 ], suggesting the improvement of glucose tolerance and prevention of the progress of insulin resistance associated with obese/diabetic through inhibition of mTOR-S6K signaling and IRS1 serine phosphorylation in adipocytes for this compound. Furthermore, evodiamine was also found to activate peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, which were considered as a potential therapeutic target in Type 2 diabetes [ 18 ].…”