Bile acids are nutrient signaling hormones

Abstract

Bile salts play crucial roles in allowing the gastrointestinal system to digest, transport and metabolize nutrients. They function as nutrient signaling hormones by activating specific nuclear receptors (FXR, PXR, Vitamin D) and G-protein coupled receptors [TGR5, sphingosine-1 phosphate receptor 2 (S1PR2), muscarinic receptors]. Bile acids and insulin appear to collaborate in regulating the metabolism of nutrients in the liver. They both activate the AKT and ERK1/2 signaling pathways. Bile acid induction of the FXR-α target gene, small heterodimer partner (SHP), is highly dependent on the activation PKCζ, a branch of the insulin signaling pathway. SHP is an important regulator of glucose and lipid metabolism in the liver. One might hypothesize that chronic low grade inflammation which is associated with insulin resistance, may inhibit bile acid signaling and disrupt lipid metabolism. The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2.

Keywords: 12α-hydroxylase; AKT; ASBT; BSEP; Bile acids; CA; CCA; CDCA; CYP27A1; CYP7A1; CYP7B1; CYP8B1; DCA; EGFR; ERK1/2; FGF15/19; FXR; G-6-Pase; G-protein coupled receptor; GCA; GDCA; GPCR; Glucose metabolism; HNF4a; Insulin; LCA; LRH-1; LXR; Liver; M1-5; NAFLD; NTCP; P13K; PEP carboxykinse; PEPCK; PKCζ; PXR; S1P; S1PR2; SHP; Sphingosine 1-phosphate receptor 2; TCA; apical sodium dependent transporter; bile salt export protein (ABCB11); chenodeoxycholic acid; cholangiocarcinoma; cholesterol 7α-hydroxylase; cholic acid; deoxycholic acid; epidermal growth factor receptor; extracellular signal-regulated kinase; farnesoid x receptor; fibroblast growth factor 15/19; glucose-6-phosphatase; glycocholic acid; glycodeoxycholic acid; hepatocyte nuclear factor 4; lithocholic acid; liver X receptor; liver-related homolog-1; muscarinic receptor 1-5; non-alcoholic fatty liver disease; oxysterol 7α-hydroxylase; phosphatidylinositol-3-kinase; pregnane X receptor; protein kinase B; small heterodimer partner; sodium taurocholate cotransporting polypeptide; sphingosine 1-phosphate; sphingosine 1-phosphate receptor 2; sterol 27-hydroxylase; taurocholate.

Figure 1. Enterohepatic circulation of bile acids

Bile acids are synthesized and conjugated mainly to glycine or taurine in hepatocytes. Bile acids travel to the gall bladder for storage during the fasting state. During digestion, bile acids travel to the duodenum via the common bile duct. 95% of the bile acids delivered to the duodenum are absorbed back into blood within the ileum and circulate back to the liver through the portal vein. 5% of bile acids are lost in feces.

Figure 2. Biosynthetic pathways of bile acids

Two major pathways are involved in bile acid synthesis. The neutral (or classic) pathway is controlled by cholesterol 7α-hydroxylase (CYP7A1) in the endoplasmic reticulum. The acidic (or alternative) pathway is controlled by sterol 27-hydroxylase (CYP27A1) in mitochondria. The sterol 12α-hydroxylase (CYP8B1) is required to synthesis of cholic acid (CA). The oxysterol 7α-hydroxylase (CYP7B1) is involved in the formation of chenodeoxycholic acid (CDCA) in acidic pathway. The neutral pathway is also able to form CDCA by CYP27A1.

Figure 3. Interrelationship between sphingosine 1-phosphate receptor 2 and the insulin signaling pathway in regulating hepatic nutrient metabolism

S1PR2, sphingosine 1-phosphate receptor 2; Src, Src Kinase; EGFR, epidermal growth factor receptor; PPARα, peroxisome proliferator-activated receptor alpha; NTCP, Na+/taurocholate cotransporting polypeptide; BSEP, bile salt export pump; PC, phosphotidylcholine; PECK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; PDK1, phosphoinositide-dependent protein kinase 1; AKT, protein kinase B; SREBP, sterol regulatory element-binding protein; PKCζ, protein kinase C zeta; FXR, farnesoid x receptor; SHP, small heterodimeric partner; MDR3, phospholipid transporter (ABCB4); GSK3β, glycogen synthase kinase 3 beta.