Bile acids in glucose metabolism in health and disease

Hagit Shapiro, Aleksandra A Kolodziejczyk, Daniel Halstuch, Eran Elinav, Hagit Shapiro, Aleksandra A Kolodziejczyk, Daniel Halstuch, Eran Elinav

Abstract

Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut microbiome configuration. Alterations in BA metabolism and signaling are associated with obesity and type 2 diabetes mellitus (T2DM), whereas treatment of T2DM patients with BA sequestrants, or bariatric surgery in morbidly obese patients, results in a significant improvement in glycemic response that is associated with changes in the BA profile and signaling. Herein, we review the roles of BAs in glucose metabolism in health and disease; highlight the limitations, unknowns, and challenges in understanding the impact of BAs on the glycemic response; and discuss how this knowledge may be harnessed to develop innovative therapeutic approaches for the treatment of hyperglycemia and diabetes.

© 2018 Shapiro et al.

Figures

Figure 1.
Figure 1.
Regulation of BA synthesis by repression of Cyp7a1 is mediated by FXR signaling. BA-FXR signaling in the liver activates SHP, which negatively controls Cyp7A1 expression. Intestinal BA-FXR signaling induces FGF15/19 expression. Release of intestinal FGF15/19 followed by binding of FGF15/19 to hepatic FGFR4/βKlotho leads to repression of hepatic Cyp7A1 and Cyp8B1.
Figure 2.
Figure 2.
BA signaling controls the systemic glycemic response. In the liver BA-FXR signaling inhibits gluconeogenesis and promotes glycogen synthesis by negative regulation of PEPCK, G6Pase, and ChREBP. In intestinal L cells, BA-TGR5 signaling leads to GLP-1 expression and secretion, whereas BA-FXR signaling inhibits GLP-1 production. The gut microbiome controls BA diversity, whereas BA composition mediates gut microbiome configuration. In the brain, BA-TGR5 signaling mediates satiety. In skeletal muscles and brown adipose tissue, BA-TGR5 sensing promotes T4 conversion to T3, leading to increased energy expenditure. In the pancreas, both BA-TGR5 and BA-FXR signaling in β cells induces insulin production. Glucose-stimulated insulin release is additionally promoted by BA-TGR5 signaling in α cells, which causes conversion of proglucagon to GLP-1 and GLP-1 release. TGR5-BA in immune cells results in inhibition of NLRP3-inflammasome and attenuated inflammation. CCL, chemokine (C-C motif) ligand; Dio2, type 2 iodothyronine deiodinase; LIP, liver inhibitory protein; T4, thyroxine; T3, tri-iodothyronine.
Figure 3.
Figure 3.
BAs and diabetes mellitus. Impaired BA signaling in the context of an altered glycemic response contributes to progression toward T2DM through multiple mechanisms.

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