Taurolithocholic acid alleviates hepatic glycolipid dysregulation in low birth weight piglets by activating HNF4α and FXR

Background Low-birth-weight (LBW) piglets often exhibit glycolipid metabolic disorders at birth, which severely impairs their postnatal growth and survival. Bile acids (BAs) act as signaling molecules that participate in the regulation of glycolipid metabolism; however, whether the hepatic metabolic abnormalities observed in LBW piglets are associated with altered BA metabolism remains largely unclear. Thus, using naturally occurring LBW fetal piglets, neonatal piglets, and hepatic cell lines as experimental models, the present study aimed to elucidate the association between bile acid homeostasis and hepatic glycolipid metabolism, and to investigate the underlying molecular mechanisms involved, through integrated analyses of bile acid-targeted metabolomics, 16S rRNA gene sequencing, and molecular docking. Result Compared with normal-birth-weight (NBW) fetal pigs, LBW exhibited a marked reduction in hepatic glycogen storage accompanied by excessive lipid accumulation. As key nuclear receptors governing glycolipid metabolism, farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) were significantly down-regulated in the liver of LBW fetal piglets at both the transcriptional and protein levels, which was coupled with impaired glycogen synthetic capacity and lipolytic capacity in these fetal pigs. Targeted bile acid metabolomic analysis revealed a profound alteration in the hepatic bile acid profile of LBW fetal pigs, characterized by an increased proportion of secondary bile acids. Notably, the hepatic level of taurolithocholic acid (TLCA) was markedly decreased in LBW fetal piglets. Further analyses demonstrated that critical processes of bile acid metabolism, including synthesis, transport, detoxification and conjugation, were impaired in LBW fetal piglets, along with disrupted endogenous TLCA biosynthesis. Mechanistically, molecular docking results suggested that TLCA might act as a potential agonist of FXR and HNF4α. In vitro assays confirmed that TLCA modulates hepatic glycolipid metabolism by activating FXR and HNF4α. More importantly, in vivo experiments indicated that exogenous supplementation of TLCA significantly ameliorated hepatic glycolipid metabolism and improved overall liver function in LBW neonatal piglets. Conclusions These findings reveal crosstalk between hepatic glucose-lipid and bile acid metabolism via HNF4α and FXR, providing potential nutritional strategies to improve liver health in LBW piglets and a theoretical basis for using BAs as feed additives in pig production.