Chitobiose exhibited a lipid-lowering effect in ob/ob -/- mice via butyric acid enrolled liver-gut crosstalk.

Chitobiose (COS 2 ) efficiently lowers lipids in vivo and facilitates butyric acid enrichment during human fecal fermentation. However, whether COS 2 can interact with butyric acid to generate a hypolipidemic effect remains unclear. This study examined the hypolipidemic mechanism of COS 2 involving butyric acid, which could alleviate non-alcoholic fatty liver disease (NAFLD). The results revealed that COS 2 administration modulated the β-oxidation pathway in the liver and restructured the short chain fatty acids in the fecal of ob/ob -/- mice. Moreover, the hypolipidemic effect of COS 2 and its specific accumulated metabolite butyric acid was verified in sodium oleate-induced HepG2 cells. Butyric acid was more effective to reverse lipid accumulation and up-regulate β-oxidation pathway at lower concentrations. Furthermore, structural analysis suggested that butyric acid formed hydrogen bonds with key residues in hydrophilic ligand binding domains (LBDs) of PPARα and activated the transcriptional activity of the receptor. Therefore, the potential mechanism behind the lipid-lowering effect of COS 2 in vivo involved restoring hepatic lipid disorders via butyric acid accumulation and liver-gut axis signaling.