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

Abstract

Low-birth-weight (LBW) piglets often exhibit glycolipid metabolic disorders at birth, which severely impair 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 pigs, neonatal piglets, and hepatic cell lines as models, the present study aimed to elucidate the association between BA homeostasis and hepatic glycolipid metabolism and to further reveal the underlying molecular mechanisms through integrated analyses of BA-targeted metabolomics, 16S rRNA gene sequencing, and molecular docking. Compared with normal-birth-weight (NBW) fetal pigs, LBW fetal pigs 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 pigs at both the transcriptional and protein levels, which was coupled with impaired glycogen synthetic capacity and lipolytic capacity in these fetal pigs. Targeted BA metabolomic analysis revealed a profound alteration in the hepatic BA profile of LBW fetal pigs, characterized by an increased proportion of secondary BAs. Notably, the hepatic level of taurolithocholic acid (TLCA) was markedly decreased in LBW fetal pigs. Further analyses demonstrated that critical processes of BA metabolism, including synthesis, transport, detoxification and conjugation, were impaired in LBW fetal pigs, 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 modulated hepatic glycolipid metabolism by activating FXR and HNF4α. More importantly, in vivo studies indicated that exogenous supplementation of TLCA significantly ameliorated hepatic glycolipid metabolism and improved overall liver function in LBW neonatal piglets. These findings reveal crosstalk between hepatic glucose-lipid and BA 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.