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

The increasing incidence of hypercholesterolemia-relateddiseaseseven in the presence of the currently available cholesterol-loweringdrugs indicates a need to discover new therapeutic drugs. This studyaimed to investigate the hypocholesterolemic potential of two triterpenoidsisolated from Protorhus longifolia stembark. In silico techniques and in vitro enzyme assays were used to evaluate the potential inhibition ofcholesterol esterase and HMG-CoA reductase by the triterpenoids (ARM-2and 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 comparedwith 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 characterizedby high intestinal absorption and lack of CYP450 enzyme inhibition.The compounds further showed, to varying degrees of efficacy, inhibitionof cholesterol micellization as well as both cholesterol esteraseand HMG-CoA reductase activities with IC50 values rangingfrom 16.4 to 41.1 & mu;M. Moreover, enhanced hepatic cellular LDLuptake and the associated upregulation of the LDL-R and SREBP-2 geneexpression were observed in the triterpenoid-treated HepG2 cells.It is evident that the triterpenoids, especially ARM-2, possess hypocholesterolemicproperties, and these molecules can serve as leads or structural templatesfor the development of new hypocholesterolemic drugs.

Automated summary

This study aimed to investigate the hypocholesterolemic potential of two triterpenoids isolated from Protorhus longifolia stembark. In silico techniques and in vitro enzyme assays were used to evaluate their potential inhibition of cholesterol esterase and HMG-CoA reductase. The results showed that both triterpenoids exhibited inhibitory effects on cholesterol esterase and HMG-CoA reductase, with promising drug-likeness properties and favorable ADMET profiles. Moreover, they enhanced hepatic cellular LDL uptake and upregulated LDL-R and SREBP-2 gene expression.