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. 2023 May 30;14:1184252. doi: 10.3389/fimmu.2023.1184252

Figure 2.

Figure 2

BAs metabolism in liver and intestine and associated therapeutic targets in PBC. The major process of BAs metabolism during synthesis in the liver and their uptake in the enterohepatic circulation provide various windows for developing effective treatments in PBC. Target locations for therapy are highlighted in red. Ursodeoxycholic acid (UDCA) is the classical treatment, and its basic mechanism is to adjust the metabolism of BAs. The first part of PBC treatment involves targeting BAs synthesis, and medication mainly targets nuclear receptors (NRs) such as farnesoid X receptor (FXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα), and constitutive androstane receptor (CAR). Primary BAs are synthesized primarily through the classic pathway, with CYP7A1 being the limiting enzyme. FXR receptors are expressed widely in hepatocytes as well as enterocytes, and BAs inhibit CYP7A1 via the induction of small heterodimer partner in hepatocytes, while in enterocytes, they induce the production of FGF-19, which acts via FGFR4 to inhibit CYP7A1 and BAs synthesis. PXR also plays a vital role in inhibiting CYP7A1. PPARα promotes BAs efflux via MDR3 and MRP3/4, detoxifying BAs and counteracting intrinsic bile toxicity by CYP3A4. The second aspect focuses on the gut-liver axis and gut microbes, including gut microbiota and apical sodium-dependent bile acid transporter (ASBT) inhibitors. Secreted BAs are actively absorbed via luminal ASBT in the distal small bowel, from where they are transported to the portal circulation via organic solute transporter (OST). The reabsorbed BAs are taken up by hepatocyte sinusoidal membrane protein NTCP and re-secreted. The third aspect targets biliary epithelial cells (BECs), as apoptosis of BECs plays an important role in PBC pathogenesis. BECs secrete inflammatory cytokines/chemokines and other antimicrobial molecules, serving as a bridge between bile acid metabolism and the immune response. BAs,Bile acids; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid; NRs,nuclear receptors; FXR, farnesoid X receptor; PXR, pregnane X receptor; PPARa, peroxisome proliferator-activated receptor alpha; CAR, constitutive androstane receptor; CYP7A1,cytochrome P450 family 7 subfamily A member 1; FGF-19,fibroblast growth factor 19; FGFR4,FGF receptor 4; MDR3,multidrug resistant protein 3; MRP3/4,multidrug resistance-related protein 3/4; CYP3A4, cytochrome P450 family 3 subfamily A member 4;ASBT,apical sodium–dependent bile acid transporter; OST, organic solute transporter; NTCP, sodium taurocholate cotransporting polypeptide; BECs,biliary epithelial cells.