Feeding stimulates gallbladder contraction emptying its cont

Feeding stimulates gallbladder contraction, emptying its contents into the upper part of the small intestine, where CBAs activate pancreatic lipase to release monoglycerides and free fatty acids from triglycerides. Mixed micelles with monoglycerides, fatty acids, cholesterol, and fat-soluble vitamins (A, D, K and E) are formed and their daidzin from the small bowel is promoted. During their passage through the small intestine, a variable portion of CBAs is deconjugated by gut bacteria to release free bile acids and glycine or taurine. Unconjugated dihydroxy bile acids and some glycine-conjugated dihydroxy bile acids are absorbed via passive diffusion from the small intestine. In the ileum, bile acids are reabsorbed efficiently (>95%) by the apical sodium-dependent bile acid transporter. Bile acids are transported into portal blood on the basolateral side of ileocytes by organic solute transporter-/β, which is a facilitated diffusion transporter. Each day, several hundred milligrams of bile acids are not absorbed by the small intestine or ileum and enter the colon, where CA and CDCA are 7α-dehydroxylated by specific anaerobic gut bacteria to form the secondary bile acids DCA and LCA, respectively. DCA and, to a much smaller extent, LCA, is absorbed passively from the colon and enters portal blood. Bile acids returning from the intestines comprise a mixture of CBAs as well as unconjugated primary and secondary bile acids. DCA can accumulate in the bile-acid pool (>50%) in some humans because DCA is not converted back to CA. Bile acids are transported actively from the blood into hepatocytes primarily by the sodium taurocholate co-transporting polypeptide SLC10A1. CBAs are again secreted from hepatocytes to stimulate bile flow. Bile acids undergo the enterohepatic circulation several times each day (Fig. 1). The enterohepatic circulation of bile acids is increased by Western-type diets high in red meat, fructose and saturated fats and low in complex carbohydrates. Each day, there is a loss of 200–600 mg of bile acids into the feces, which is replaced by increased synthesis of bile acids in the liver.
Interplay between bile acids, insulin and FXR in the regulation of hepatic metabolism Since 2002 it has been known that bile acids activate different signaling pathways (ERK1/2, AKT, c-Jun N-terminal kinase (JNK)1/2, protein kinase C (PKC)) in the liver and that CBAs and free BAs activate these pathways by different mechanisms. In 2005, it was reported that taurocholic acid (TCA), but not DCA, activates the ERK1/2 and AKT signaling pathways in primary hepatocytes via a pertussis toxin (PTX)-sensitive mechanism, which suggests a role for a Gαi-linked GPCR in this signaling pathway. Nevertheless, activation of the AKT signaling pathway by TCA or DCA in primary rodent hepatocytes was shown to activate the activity of glycogen synthase significantly to the same extent as that observed with insulin alone. Interestingly, the addition of DCA or TCA plus insulin resulted in an additive effect on AKT activation and the activity of glycogen synthase in primary hepatocytes in vivo. Bile acids also down-regulated expression of mRNA of the gluconeogenic genes PEPCK and G-6-Pase in primary rat hepatocytes in vivo in a manner similar to that observed with insulin. The down-regulation of expression of gluconeogenic genes by TCA was blocked by PTX in primary rat hepatocytes (PRHs). Finally, in PRHs, TCA plus insulin showed stronger inhibition of the secretion/synthesis of glucose than TCA alone or insulin alone. In total, these results suggest that bile acids may “collaborate” with insulin to regulate glucose metabolism in the liver after consumption of a meal. This is a reasonable hypothesis because bile acids and co-absorbed nutrients returning from the intestines along with insulin secretion appear to be regulated in a coordinated manner. Activation of the AKT signaling pathway appears to be important for FXR activation by bile acids. In 2010, it was reported that wortmannin (an inhibitor of the phosphoinositide 3-kinase (PI3K) signaling pathway) significantly inhibited the induction of expression of small heterodimeric partner (SHP) mRNA by TCA in PRHs. SHP is a key FXR target gene that is induced by most bile acids. Further studies showed that chemical inhibition or knockdown of PKCζ mRNA significantly inhibited the ability of TCA to induce SHP. PKCζ is activated by phosphoinositide-dependent protein kinase-1, which is activated by PI3K (a kinase in the insulin signaling pathway). Moreover, it has been reported that PKCζ can phosphorylate FXR, possibly allowing this NR to be translocated to the nucleus and to induce the expression of genes involved in the metabolism of bile acids, glucose and lipids. Moreover, other PKC isoforms activated by bile acids have been reported to phosphorylate FXR. These studies indicate a physiologic link between cell-signaling pathways (AKT, PKC) and a NR (FXR) in coordination with nutrient metabolism in the liver.