Taurodeoxycholic, taurocholic, and glycocholic acids promote hepatic gluconeogenesis via TGR5 in dairy cows

Abstract

Ruminants and monogastric animals exhibit significant differences in gluconeogenic efficiency. In dairy cows, hepatic gluconeogenesis serves as the primary source of glucose. Metabolites modulate gluconeogenesis efficiency through allosteric regulation, redox state, and signal transduction pathways. However, the liver-enriched metabolites that regulate hepatic gluconeogenesis in dairy cows and their specific regulatory mechanisms remain incompletely characterized. Six Holstein dairy cows and six Duroc × (Landrace × Yorkshire) (DLY) crossbred pigs served as research subjects. Employing non-targeted and targeted metabolomics, we discovered that three bile acids—taurodeoxycholic acid (TDCA), taurocholic acid (TCA), and glycocholic acid (GCA)—were highly enriched in Holstein dairy cows’ livers. In bovine hepatocytes, individual or combined stimulation of these bile acids significantly upregulated the expression of gluconeogenesis genes (FBP1, PCK1 and G6PC) and enhanced glucose production. In fasting mice with induced gluconeogenesis, TDCA, TCA, and GCA increased fasting blood glucose levels, and pyruvate tolerance tests further revealed their capacity to enhance hepatic gluconeogenesis, enabling more efficient glucose synthesis from pyruvate. Mechanistically, these bile acids activated Takeda G protein-coupled receptor 5 (TGR5), elevated intracellular cAMP levels, and ultimately enhanced gluconeogenesis via the transcription factor cAMP-response element binding protein (CREB). Notably, a TGR5 inhibitor abrogated the stimulatory effects of TDCA, TCA, and GCA on hepatic gluconeogenesis in fasting mice. TDCA, TCA, and GCA are key metabolites promoting hepatic gluconeogenesis in dairy cows, with TGR5 as the pivotal receptor and the cAMP/PKA/CREB pathway as the critical downstream mechanism.