Insights into the Hypolipidemic Action Mechanism of a Birch-derived Polysaccharide: From Molecular Dynamics to In vivo Efficacy

This study aimed to elucidate the lipid-lowering mechanisms of L-rhamnopyranosyl-6-alkyl-D-galacturonan (L-RDG) – a polysaccharide from Betula pendula leaves – focusing on bile acid (BA) sequestration and modulation of cholesterol metabolism. L-RDG was extracted, purified, and structurally characterized (FTIR, GC, HPSEC). In vivo efficacy was assessed in 48 hyperlipidemic Wistar rats fed a high-fat diet (HFD) divided into: HFD control (n=12), HFD + L-RDG (3 g/100g diet, n=12), HFD + cholestyramine (2 g/100g diet, n=12), and normal diet control (n=12). BA-binding capacity was evaluated in vitro; molecular dynamics simulations explored L-RDG-BA interactions. Hepatic CYP7A1 and LDLR mRNA expression was analyzed via RT-PCR. L-RDG significantly reduced serum and hepatic lipid levels in HFD-fed rats. L-RDG reduced serum LDL-C by 42.1% (p<0.001) and hepatic triglycerides by 32.5% (p=0.005), matching cholestyramine (p>0.05). It demonstrated selective BA-binding (highest affinity for deoxycholic acid, p=0.004) and increased fecal BA excretion by 135.8% (p<0.001). Molecular simulations identified hydrogen bonding as the primary interaction mechanism. L-RDG upregulated CYP7A1 (p<0.001) and LDLR (p<0.001) expression. L-RDG demonstrates potent lipid-lowering activity through BA sequestration and modulation of cholesterol metabolism pathways. Its efficacy parallels cholestyramine, with dual mechanisms involving fecal BA excretion and transcriptional regulation of key hepatic genes. These findings position L-RDG as a promising natural candidate for dyslipidemia management, warranting further clinical evaluation. The actual work was carried out within the framework of state task number 056-00065-25-03.