Triterpenoids from Protorhus longifolia Exhibit Hypocholesterolemic Potential via Regulation of Cholesterol Biosynthesis and Stimulation of Low-Density Lipoprotein Uptake in HepG2 Cells.

Autor: Ndlovu M; Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Hatfield 0028, South Africa., Serem JC; Department of Anatomy, University of Pretoria, Pretoria 0007, South Africa., Selepe MA; Department of Chemistry, University of Pretoria, Hatfield 0028, South Africa., Opoku AR; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa., Bester MJ; Department of Anatomy, University of Pretoria, Pretoria 0007, South Africa., Apostolides Z; Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Hatfield 0028, South Africa., Mosa RA; Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Hatfield 0028, South Africa.
Jazyk: angličtina
Zdroj: ACS omega [ACS Omega] 2023 Aug 14; Vol. 8 (34), pp. 30906-30916. Date of Electronic Publication: 2023 Aug 14 (Print Publication: 2023).
DOI: 10.1021/acsomega.3c01995
Abstrakt: The increasing incidence of hypercholesterolemia-related diseases even in the presence of the currently available cholesterol-lowering drugs indicates a need to discover new therapeutic drugs. This study aimed to investigate the hypocholesterolemic potential of two triterpenoids isolated from Protorhus longifolia stem bark. In silico techniques and in vitro enzyme assays were used to evaluate the potential inhibition of cholesterol esterase and HMG-CoA reductase by the triterpenoids (ARM-2 and RA-5). The toxicity, modulation of low-density lipoprotein (LDL) uptake, and associated gene expression were determined in HepG2 hepatocytes. In silico molecular docking revealed that ARM-2 compared with RA-5 has a relatively stronger binding affinity for both enzymes. Both triterpenoids further demonstrated promising in silico drug-likeness properties and favorable ADMET profiles characterized by high intestinal absorption and lack of CYP450 enzyme inhibition. The compounds further showed, to varying degrees of efficacy, inhibition of cholesterol micellization as well as both cholesterol esterase and HMG-CoA reductase activities with IC 50 values ranging from 16.4 to 41.1 μM. Moreover, enhanced hepatic cellular LDL uptake and the associated upregulation of the LDL-R and SREBP-2 gene expression were observed in the triterpenoid-treated HepG2 cells. It is evident that the triterpenoids, especially ARM-2, possess hypocholesterolemic properties, and these molecules can serve as leads or structural templates for the development of new hypocholesterolemic drugs.
Competing Interests: The authors declare no competing financial interest.
(© 2023 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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