Lipophilic Grape Seed Proanthocyanidin Attenuates High-Fat Diet-Induced Hyperlipidemia by Modulating Gut Microbiota and Metabolic Profiles

Obesity is a serious global health concern driven by unhealthy diets. Lipophilic grape seed proanthocyanidin (LGSP) has demonstrated potential lipid-lowering properties, yet its underlying mechanisms remain incompletely elucidated. This study investigated the antihyperlipidemic effects of LGSP in high-fat diet (HFD)-fed mice. LGSP supplementation attenuated HFD-induced obesity, organ hypertrophy, fat accumulation, liver injury, and hepatic inflammation. Gut microbiota analysis revealed that LGSP significantly increased microbial abundance and diversity in HFD-fed mice and positively reshaped the gut flora structure by decreasing the Firmicutes/Bacteroidetes ratio. Integrated serum metabolomic and liver transcriptomic analyses identified key regulators involved in lipid metabolism, including palmitoylcarnitine, hydrocortisone, acitretin, embelin, and 1-(11Z-eicosenoyl)-glycero-3-phosphate, as well as the genes Serpina3n and Acnat2. Further validation confirmed that LGSP enhances bile acid metabolism, promotes thermogenesis, and improves energy metabolism. These findings underscore the potential of LGSP as an effective functional food component for managing hyperlipidemia.