FXR inhibits BA synthesis by inducing small heterodimer partner (SHP), a nuclear receptor that lacks a ligand-binding domain [84]. SHP interacts with and represses nuclear receptors and transcription factors, including PXR, CAR, LXR, GR, and FXR [85,86]. SHP also inhibits the activation of liver receptor homolog-1 (LRH-1), which induces CYP7A1, the key enzyme responsible for BA synthesis from cholesterol [87] (Figure 1A). Furthermore, FXR also inhibits the expression of CYP7A1 by inducing fibroblast growth factor (FGF) 15/19 (mouse FGF15 and human FGF19) and β-Klotho (βKL). βKL forms binary complexes with FGF receptor 4 (FGFR4) to function as a coreceptor of FGFR4 for FGF15/19 [88]. Transcription factor EB (TFEB) is activated by dephosphorylation and induces CYP7A1. After activating FGFR4/βKL by FGF15/19, the mechanistic target of rapamycin phosphorylates and inactivates TFEB, leading to CYP7A1 repression [89]. FGF15/19 also stabilizes SHP, which represses CYP7A1 and CYP8B1. CYP8B1 is a key enzyme for the synthesis of CA. The binding of FGF15 to FGFR4 activates the Hippo signaling pathway. In the Hippo signaling pathway, SHP is phosphorylated and stabilized by mammalian sterile 20-like kinase 1 (Mst1) and Mst2, homologs of the Hippo kinase in Drosophila [90] (Figure 1B). FXR also regulates BA transporters. FXR represses NTCP in the liver, leading to a reduction of the hepatic uptake of Bas [91]. On the other hand, FXR enhances BA efflux into the liver by inducing BSEP and OSTα/β [92,93]. Overall, FXR reduces excess Bas in the liver. Although TGR5 is weakly expressed in the liver, TGR5-knockout mice exhibit a decrease in total BA pool size [94]. Additionally, TGR5-knockout mice exhibit reduced levels of CYP7B1 and increased levels of secondary and hydrophobic Bas [95,96,97]. PXR is activated by LCA [98,99] and PXR regulates the expression of CYP3A and CYP2B, which convert LCA to hyocholic acid (HCA) and UDCA [100,101,102]. In addition, PXR indirectly suppresses the expression of CYP7A1 by inhibiting the activation of hepatocyte nuclear factor 4α, which upregulates the expression of CYP7A1 [103,104]. VDR is also activated by LCA and its metabolite, 3-keto LCA [105,106], and LCA induces the expression of CYP3A [106,107,108]. LXRα is weakly activated by hyodeoxycholic acid (HDCA) [109]. The BA pool size and its excretion are decreased in LXRα-knockout mice. LXRα-knockout mice also exhibit reduced CYP7A expression [110], but LXRβ-knockout mice do not [111].

Glucose and insulin upregulate and downregulate FXR expression, respectively, and FXR is associated with glucose metabolism [112,113]. The association between FXR and glucose metabolism is differently affected by the fed and fasting states. In the fed state, treatment of wild-type mice with the FXR ligand decreases the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). PEPCK and G6Pase are essential for the upregulation of gluconeogenesis. In contrast, treatment of wild-type mice in the fasting state with FXR ligand increases the expression of PEPCK and G6Pase. FXR-knockout mice exhibit decreased blood glucose levels, and PEPCK and G6Pase expression are downregulated. The effects of FXR with the FXR ligand are mediated by GR [114]. The treatment of wild-type mice with CA reduces blood glucose levels and PEPCK and GP6ase expression. Furthermore, the treatment of SHP-knockout mice with CA increases blood glucose levels. Thus, the blood glucose-lowering effect of FXR is, at least in part, mediated by SHP [115]. FXR also inhibits PEPCK and G6Pase expression by inducing FGF15/19. FGF15/19 inactivates the cAMP regulatory element-binding protein (CREB), the transcription factor that induces peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α) [116]. PGC-1α is a coactivator that induces the expression of genes involved in metabolic pathways and mitochondria by interacting with a variety of nuclear receptors [117,118]. FXR interacts with the carbohydrate responsive element binding protein (ChREBP) and suppresses the activity of ChREBP. ChREBP is a transcription factor that regulates the expression of genes controlling glycolysis and lipogenesis. ChREBP upregulates the expression of L-pyruvate kinase (L-PK), a key enzyme for glycolysis [119]. Activated FXR releases ChREBP and its coactivators (p300 and CREB-binding protein) from the L-PK promoter region and inhibits L-PK expression [120]. FXR and CDCA induce glucose transporter 4 expression in differentiated 3T3-L1 adipocytes and the hepatic cell line HepG2 [121]. FXR increases glucose-stimulated insulin secretion and expression by inducing the KLF11 transcription factor [113]. Although CDCA increases the glucose-stimulated secretion of insulin from wild-type mice, FXR-knockout mice are unaffected [122].

TGR5 activation increases the intestinal level of GLP-1 [123,124,125,126,127]. LCA, taurodeoxycholic acid (TDCA), and TLCA increases GLP-1 secretion via TGR5 activation [123,125]. GLP-1 release is mediated by TGR5 located in the basolateral membrane of L-cells [125]. Most active GLP-1 is degraded in the intestine and liver and 10–15% of secreted GLP-1 from the intestine reaches the pancreas via the systemic circulation [128]. GLP-1 induces the release and synthesis of insulin in β-cells in the pancreatic islets. The binding of GLP-1 to GLP-1 receptor activates adenylate cyclase, leading to increased cAMP levels. PKA and EPAC are then activated, which induces an increase in intracellular Ca²⁺ from the ER and extracellular sources via voltage-dependent Ca²⁺ channels [128,129]. Additionally, the activation of PKA by GLP-1 leads to the activation of pancreatic duodenal homeobox-1 protein (PDX-1), which binds to the promoter of the gene encoding insulin and induces the synthesis of insulin [128,130] (Figure 2). In contrast to TGR5, FXR suppresses GLP-1 production in L-cells by inhibiting the activity of ChREBP, which induces the expression and secretion of GLP-1 in L-cells [120,131]. Furthermore, the level of serum HCA is lower in diabetics and people with a high body mass index [132,133,134]. HCA induces GLP-1 by activating TGR5 and inhibiting FXR, and TGR5 activation increases serum insulin and decreases blood glucose levels [132].

Dietary lipids (triglycerides [TGs], cholesterol, and phospholipids) are absorbed and incorporated into chylomicrons in the intestine. Chylomicrons are then converted to very low-density lipoprotein (VLDL) in the liver. VLDL transports lipids from the liver to the systemic circulation. VLDL is then converted to HDL and returned to the liver [135]. In the process of lipogenesis, acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA, and fatty acid synthase (FAS) converts malonyl-CoA to palmitate. Stearoyl-CoA desaturase (SCD) mediates the conversion of saturated fatty acids (FAs) to monounsaturated FAs, and the newly-produced FAs are then stored as TGs. Sterol regulatory element-binding protein 1C (SREBP1C) is a transcription factor that induces lipogenic genes, including FAS, ACC, and SCD [136,137]. FXR-knockout mice exhibit an increase in SREBP1C, SCD-1, and FAS and also exhibit increased levels of serum and liver TGs, serum cholesterols, and serum free FAs (FFAs) [115]. Additionally, CA feeding decreases the serum levels of TGs, cholesterol, and FFAs in mice [115,138]. CA and CDCA decrease the expression of FAS, ACC, SCD, and SREBP1C [138]. SHP induced by FXR suppresses lipogenesis by suppressing lipogenic genes via the inhibition of LXR, which induces SREBP1C expression [138,139]. Furthermore, FXR induces the expression of carboxylesterase 1 (CES1), which reduces hepatic TGs by inducing TG hydrolysis to release FFAs. Released FFAs activate PPARα, leading to the enhancement of FA oxidation [140,141].