Xia Ku Cao Paste restores intestinal microbiota homeostasis and improves hepatic metabolism disturbances to alleviate hyperlipidemia.

UPLC-Q-TOF-MS/MS analysis identified 75 chemical components in XKCP, with 21 prototype compounds absorbed into the bloodstream and 18 metabolites detected as blood-entry components.

• Chemical characterization was performed using UPLC-Q-TOF-MS/MS technology
• 75 total components were identified in XKCP
• 21 of these were prototype compounds found in blood
• 18 additional blood-entry components were identified as metabolites

XKCP significantly regulated serum lipid levels and ameliorated hepatic steatosis and damage in HFD-induced hyperlipidemic rats.

• A high-fat diet (HFD)-induced hyperlipidemia rat model was used for in vivo assessment
• Serum biochemistry and histopathological analysis were employed to evaluate therapeutic efficacy
• XKCP treatment attenuated inflammatory and oxidative responses in HLP rats
• Liver proteomics was used to further elucidate pathways of action

XKCP ameliorated gut microbiota dysbiosis in HLP rats, notably affecting Firmicutes, Bacteroidetes, and genera including Clostridium, Bacteroidetes, and Akkermansia myxophila.

• Gut microbiota analysis was performed to characterize compositional changes
• Firmicutes and Bacteroidetes at the phylum level were notably affected by XKCP treatment
• At the genus level, Clostridium, Bacteroidetes, and Akkermansia myxophila were significantly modulated
• Correlation analysis showed significant correlations between XKCP-induced changes in gut microbiota and metabolite profiles

XKCP markedly reduced serum stearic acid and oleic acid concentrations while modulating key fatty acid biosynthetic and metabolic pathways.

• Free fatty acid (FFA) quantification was used to measure serum fatty acid levels
• Stearic acid and oleic acid were specifically identified as reduced by XKCP treatment
• Key fatty acid biosynthetic and metabolic pathways were modulated by XKCP

XKCP increased levels of beneficial short-chain fatty acids (SCFAs) in the gut, including hexanoic acid, isobutyric acid, isovaleric acid, valeric acid, and 2-methylbutyric acid.

• SCFA quantification was performed to assess gut metabolite changes
• Five specific beneficial SCFAs were identified as increased: hexanoic acid, isobutyric acid, isovaleric acid, valeric acid, and 2-methylbutyric acid
• SCFA changes correlated significantly with gut microbiota composition changes induced by XKCP

XKCP mechanistically targeted the SCAP/SREBP-2 pathway to regulate cholesterol levels and sustain cholesterol homeostasis.

• SCAP/SREBP-2 pathway-specific inhibitor interference was used to confirm pathway involvement
• Molecular docking was employed to evaluate interactions between XKCP components and pathway targets
• Modulation of the SCAP/SREBP-2 pathway was identified as correcting metabolic disorders associated with hyperlipidemia

Rosmarinic acid and chrysoeriol were identified as the potential active components of XKCP responsible for anti-hyperlipidemic effects, significantly attenuating sodium oleate-induced lipid accumulation in HepG2 cells.

• Sodium oleate (SO)-induced HepG2 cells served as the in vitro model
• Both XKCP and its individual components rosmarinic acid and chrysoeriol significantly attenuated lipid accumulation
• These findings were consistent with in vivo observations in HFD-induced HLP rats
• Rosmarinic acid and chrysoeriol were among the 21 prototype compounds identified as blood-entry components