Soaping Up Type 2 Diabetes With Bile Acids?
The Link Between Glucose and Bile Acid Metabolism in Humans Tightens: Quality Matters!
- European Genomic Institute for Diabetes (EGID), FR 3508, F-59000, Lille, France; Université Lille II, F-59000, Lille, France; INSERM UMR 1011, F-59000, Lille, France; and the Institut Pasteur de Lille, F-59000, Lille, France
- Corresponding author: Bart Staels, .
Bile acids (BA) are amphipathic molecules whose physicochemical properties facilitate the solubilization of biliary cholesterol and intestinal lipids. As detergents, excessive concentrations of BA, such as in cholestatic diseases, are toxic, imposing a tight control of BA pool size and in particular its hydrophobicity level. Hence, BA synthesis is under negative control by BA themselves, which act as signaling molecules via specific pathways, including the G protein–coupled BA receptor (TGR5) and the nuclear receptors farnesoid X receptor (FXR), vitamin D receptor, and pregnane X receptor as well as different kinase signaling pathways. Recently, BA were identified as regulators of glucose, lipid, and energy metabolism with unexpected roles for TGR5 and FXR therein (1).
BA are synthesized from cholesterol by the hepatic parenchymal cells through the classical and alternative pathways with cholesterol 7 α-hydroxylase (Cyp7a1) and cholesterol 27 α-hydroxylase (Cyp27a1) as first enzymes, respectively. In humans, the ratio of the primary BA cholic acid (CA)/chenodeoxycholic acid (CDCA) determines the hydrophobicity of the BA pool, a step regulated by the activity of cholesterol 12α-hydroxylase (Cyp8b1), which adds an additional OH group at C12 (Fig. 1). CDCA and CA are conjugated to glycine or taurine and secreted via the bile canaliculus into the intestine, where they are transformed through dehydroxylation by the intestinal flora into the more hydrophobic secondary BA lithocholic acid (LCA) and deoxycholic acid (DCA), respectively, before returning to the liver via the enterohepatic cycle. The expression and activity of the hepatic BA synthesis enzymes is negatively controlled by BA acting via FXR in both intestine (via FGF19 …