Figure 5.

Farnesoid X receptor (FXR) regulates enterohepatic circulation of bile acids. Major bile acid transporters in human hepatocytes and enterocytes are shown. Enzymes and transporters regulated by FXR are indicated. In hepatocytes, bile acids activate FXR to inhibit CYP7A1 gene transcription by two pathways: (i) FXR induces small heterodimer partner (SHP), which inhibits CYP7A1 by inhibiting nuclear receptors liver related homologue-1 (LRH-1) or hepatocyte nuclear factor (HNF4), which bind to the CYP7A1 promoter. (ii) In enterocytes, FXR induces intestinal hormone fibroblast growth factor 19 (FGF19), which is circulated to hepatocytes to activate FGF receptor 4 (FGFR4) signaling to inhibit CYP7A1 via activation of the extracellular stress-activated receptor kinase 1/2 (ERK1/2) pathway. FXR induces bile salt expert pump (BSEP) to efflux bile acids into bile; multidrug resistance protein 2/3 (MDR2/3) to efflux phosphatidylcholine (PC) to bile; and MDR related protein 2 (MRP2) to efflux organic anions including glucuronidated- and sulfated-bile acids, organic anions, and drugs into bile. Bile acids also facilitate efflux of cholesterol to bile by ATP binding casette G5/G8(ABCG5/G8). In the bile, bile acids, PC, and cholesterol form mixed micelles, which are stored in the gallbladder. In the brush border membrane of the ileum, bile acids are reabsorbed by the apical sodium bile salt transporter (ASBT). In enterocytes, bile acids activate FXR, which induces ileum bile acid binding protein (IBABP) to bind bile salts and may facilitate intracellular transport of bile acids to organic solute transporter α/β (OSTα/β) located in the basolateral membrane for efflux of bile acids into portal circulation. Bile acids in portal blood are reabsorbed into hepatocytes by Na⁺-dependent taurocholate cotransport peptide (NTCP). FXR inhibits NTCP transcription as a feedback inhibition of bile acid uptake to prevent liver injury. In the sinusoidal membrane of enterocytes and hepatocytes, FXR also induces MRP3/4 to efflux bile acids as an adaptive response to cholestasis. In hepatocytes, FXR also induces OSTα/β to efflux bile acids into sinusoidal blood to prevent bile acid accumulation in hepatocytes. MRP3 may be induced by FXR as an adaptive response to cholestasis. Bile acids returned to hepatic sinusoid are also taken up by Na⁺-independent organic anion transport proteins (OATP2). Many of these membrane transporters (ASBT, OSTα/β, and MRP2/3) also are present in cholangiocytes for reabsorption of bile acids, and in renal proximal tubule cells for reabsorption of bile acids from blood circulation and excretion of hydrophilic bile acids.