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

TL;DR

This study identifies three bile acids that boost glucose production in dairy cows by activating a specific liver receptor.

Contribution

The study reveals novel bile acids and their mechanism via TGR5 for enhancing hepatic gluconeogenesis in dairy cows.

Findings

TDCA, TCA, and GCA upregulate gluconeogenesis genes in bovine hepatocytes.

These bile acids increase fasting blood glucose and enhance glucose synthesis from pyruvate in mice.

TGR5 activation and the cAMP/PKA/CREB pathway mediate the effects of these bile acids.

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.

The online version contains supplementary material available at 10.1186/s40104-025-01275-w.

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