Bile acids as regulatory molecules

Abstract

In the past, bile acids were considered to be just detergent molecules derived from cholesterol in the liver. They were known to be important for the solubilization of cholesterol in the gallbladder and for stimulating the absorption of cholesterol, fat-soluble vitamins, and lipids from the intestines. However, during the last two decades, it has been discovered that bile acids are regulatory molecules. Bile acids have been discovered to activate specific nuclear receptors (farnesoid X receptor, preganane X receptor, and vitamin D receptor), G protein coupled receptor TGR5 (TGR5), and cell signaling pathways (c-jun N-terminal kinase 1/2, AKT, and ERK 1/2) in cells in the liver and gastrointestinal tract. Activation of nuclear receptors and cell signaling pathways alter the expression of numerous genes encoding enzyme/proteins involved in the regulation of bile acid, glucose, fatty acid, lipoprotein synthesis, metabolism, transport, and energy metabolism. They also play a role in the regulation of serum triglyceride levels in humans and rodents. Bile acids appear to function as nutrient signaling molecules primarily during the feed/fast cycle as there is a flux of these molecules returning from the intestines to the liver following a meal. In this review, we will summarize the current knowledge of how bile acids regulate hepatic lipid and glucose metabolism through the activation of specific nuclear receptors and cell signaling pathways.

Fig. 1.

Pathways of bile acid biosynthesis in the liver. The neutral and alternative pathways of bile acid biosynthesis are initiated by cholesterol 7α-hydroxylase (CYP7A1) and mitochondrial sterol 27-hydroxylase (CYP27A1), respectively. Sterol 12α-hydroxylase (CYP8B1) determines the ratio of cholic acid to chenodeoxycholic acid synthesized. In humans, the neutral pathway is the major pathway of synthesis under normal physiological conditions. StAR D1, steroidogenic acute regulatory protein D1; 27OH-C, 27-hydroxycholesterol; 25OH-C, 25-hydroxycholesterol; SULT2B1b, hydroxycholesterol sulfotransferase 2B1b; CYP7B1, oxysterol 7α-hydroxylase; BAL, bile acid CoA ligase; BAT, bile acid CoA:amino acid N-acyltransferase.

Fig. 2.

Enterohepatic circulation of bile acids. Conjugated bile acids (Conj-BA) are actively transported from the canalicular side of the hepatocyte by the bile salt export pump (BSEP; ABC B11) along with phospholipids (PL; ABC 4) and cholesterol (C; ABC G5/G8). Conjugated bile acids are actively transported into ileocytes by the sodium-dependent intestinal bile acid transporter (IBAT). Inside the ileocyte, bile acids induce the synthesis of fibroblast growth factor 15/19 (FGF-15/19) but are also bound by the intestinal bile acid binding protein (I-BABP). They exit the ileocyte on the basolateral side via the heterodimeric organic solute transporter (Ost-α/β). Bile acids and FGF-15/19 are transported back to the liver via the portal blood. Conjugated bile acids are actively transported into the hepatocyte primarily by the Na⁺/taurocholate cotransporting polypeptide (NTCP). FGF-15/19 binds to and activates hepatic fibroblast growth factor receptor 4 (FGFR4), which in turn activates the JNK signaling pathway. Activation of JNK downregulates the gene encoding cholesterol 7α-hydroxylase (CYP7A1), inhibiting bile acid synthesis.

Fig. 3.

Downregulation of cholesterol 7α-hydroxylase (CYP7A1) by bile acids, cytokines, and FGF-15/19. Bile acids are transported into the hepatocyte via the Na⁺/taurocholate cotransporting polypeptide (NTCP). In vitro, bile acids activate ASM-generating ceramide, which causes the clustering and activation of the FAS receptor. This receptor then activates the JNK signaling pathway. Activation of the JNK 1/2 pathway by bile acids, TNF-α, IL-1, or fibroblast growth factor-15/19 (FGF-15/19) is hypothesized to result in the phosphorylation of HNF4α, decreasing its ability to activate the gene encoding CYP7A1. BARE, bile acid-responsive element; MKK4/7, MAP kinase kinase 4/7; RXR, retinoid X receptor.

Fig. 4.

Structures of unconjugated primary and secondary bile acids in humans. Cholic acid (CA; 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid) and chenodeoxycholic acid (CDCA; 3α,7α-dihydroxy-5β-cholan-24-oic acid) are synthesized from cholesterol in the liver hepatocytes. Deoxycholic acid (DCA; 3α,12α-dihydroxy-5β-cholan-24-oic acid) and lithocholic acid (LCA; 3α-hydroxy-5β0cholan-24-oic acid) are synthesized from cholic acid and chenodeoxycholic acid, respectively, by a small population of 7α-dehydroxylating intestinal anaerobic bacteria.

Fig. 5.

Major cell signaling pathways activated by bile acids in hepatocytes. Components of the JNK 1/2, extracellular-regulated kinases (ERK 1/2), and Ser/Thr kinase Akt/PKB (protein kinase B) signaling pathways are shown. Each signaling pathway consists of three sequentially acting kinases. GS, glycogen synthase; GSK-3, glycogen synthase kinase 3; PI3K, phosphoinositide-3-kinase; PDK-1, phosphoinositide-dependent protein kinase 1; Erb1/2/3, epidermal growth factor receptor family members; Rac/Rho;Cdc-42, small molecular weight GTP/GDP binding proteins involved in activating JNK 1/2 pathway; K-Ras and H-Ras, small molecular weight GTP/GDP binding proteins associated with activation of ERK 1/2 pathway; p90 rsk, p90 ribosomal 6 kinase; Ets, ETS domain transcription factor; CREB, c-AMP-responsive element binding protein; C/EBPβ, CCAAT enhancer binding protein β; GPCRs, G-protein-coupled receptors; FGF-R4, fibroblast growth factor receptor 4; TNF-R, tumor necrosis factor receptor; IL-1 R, interleukin 1 receptor; Fas-R, Fas receptor.

Fig. 6.

Activation of the Akt (insulin signaling pathway) and FXR by bile acids in hepatocytes. Taurocholate (TCA) activates the AKT pathway via a Gα_i protein;coupled receptor(s). Phosphoinositide-dependent protein kinase 1 (PDK-1), a kinase in the insulin signaling pathway, then activates atypical protein kinase C ζ (PKCζ). Activated PKCζ is proposed to phosphorylate FXR, enhancing its ability to bind TCA and induce the gene encoding SHP. Activated Akt phosphorylates the transcription factor FOX01. The phosphorylated form of FOX01 exits the nucleus, allowing for the downregulation of gluconeogenic genes [PEP carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase)]. Akt also phosphorylates glycogen synthase kinase 3 (GSK-3), inactivating this kinase, which allows for the dephosphorylation and activation of glycogen synthase activity. NTCP, Na⁺/taurocholate cotransporting polypeptide; DCA, deoxycholic acid; Src, src family kinases; EGFR, epidermal growth factor receptor; PTP, phosphotyrosine phosphatase; PTX, pertussis toxin; IR, insulin receptor.

Fig. 7.

Regulation of hepatic glucose metabolism and cholesterol and fatty acid biosynthetic pathways by bile acids. Bile acids regulate glucose metabolism in hepatocytes by activating the insulin signaling pathway and by induction of the gene encoding SHP. Conjugated bile acids activate the insulin signaling pathway (pAKT) via surface G-protein-coupled receptors (GPCRs), which activates glycogen synthase activity and inhibits gluconeogenesis by phosphorylation of FOX01. SHP is known to interact with FOX01, a transcription factor known to upregulate gluconeogenic genes. Phosphoinositide-dependent protein kinase 1 (PDK-1), a kinase in the insulin signaling pathway, is known to phosphorylate and activate protein kinase Cζ (PCKζ). PKCζ is proposed to phosphorylate FXR, enhancing the ability of conjugated bile acids to induce the gene encoding SHP. SHP can also downregulate the gene encoding SREBP1-c, which controls the rate of FA synthesis. Bile acids can activate JNK 1/2 in hepatocyte cultures by stimulating ceramide synthesis. In vivo, bile acids can activate the JNK 1/2 pathway by stimulating the synthesis of fibroblast growth factor 15/19 (FGF-15/19) in the intestines. Finally, TNF-α and IL-1 can also activate the JNK 1/2 pathway downregulating CYP7A1. Bold lines indicate pathways activated by bile acids.