A Neutral Triple-Helix Pomegranate (Punica granatum) Peel Polysaccharide with Lipid-Lowering and Prebiotic Activities

A homogeneous neutral polysaccharide (PPP-1; 1.5 × 10⁴ Da) was isolated from pomegranate peel and characterized as a glucose-rich glucan with α-/β-pyranose linkages and a triple-helix conformation. PPP-1 improved lipid dysregulation in oleic acid-treated HepG2 cells, reducing total cholesterol and triglycerides (TG) by up to 76.2 and 70.4%, respectively, and lowering low-density lipoprotein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C), accompanied by suppression of SREBP-1c and FAS via SIRT1/AMPK activation. In high-fat diet (HFD)-fed mice, PPP-1 reduced weight gain and epididymal fat by 42.1 and 41.5%, alleviated hepatic steatosis, and lowered alanine aminotransferase/aspartate aminotransferase by 27.9 and 32.1% without affecting food intake. PPP-1 also corrected HFD-induced dyslipidemia, increasing HDL-C by 36.4% and reducing TG and LDL-C by 37.0% and 35.4%. PPP-1 lowered the Firmicutes/Bacteroidetes ratio and enriched Lactobacillus and Bifidobacterium. Metabolomics confirmed normalization of obesity-related metabolites and modulation of lipid-related pathways. These findings identify PPP-1 as a dual-acting hepatic and prebiotic polysaccharide with promise for metabolic health.