is present. The process of bile formation depends on the liver synthesis and the canalicular secretion of BAs. The active transport of BAs across the canalicular membranes of hepatocytes is a primary driving force for bile flow. The majority of the BAs in the intestine are absorbed intact. Approximately 15% are deconjugated by the bacterial flora in the distal small intestine, with the production of “secondary” BAs by the conversion of CA to deoxycholic acid and of CDCA to lithocholic acid. Most of the conjugated and deconjugated BAs are reabsorbed in the distal intestine and undergo enterohepatic circulation that maintains the BA pool. Thus, at least 12 major conjugated primary and secondary bile salt species are contained in human bile, although primary bile salts are usually predominant.
Enterohepatic Bile Acid Circulation
BAs undergo an enterohepatic circulation that depends on active transport systems in the liver and the intestine (Figure 1.2). More specifically, BAs are excreted from hepatocytes into bile through BSEP/ABCB11 at the bile canaliculus, reabsorbed in the ileum by the apical sodium‐dependent bile salt transporter (ASBT/SLC10A2), and return through the portal blood to the liver, where they are taken up by hepatocytes via the basolateral transport systems NTCP/SLC10A1 for conjugated BAs and OATPs/SLCO/SLC21 family for unconjugated BAs, thus limiting the amount of BA spillover into the systemic circulation. BAs complete the enterohepatic circulation six to eight times a day and are highly efficiently conserved. BAs that escape ileal reabsorption reach the colon, where they are deconjugated and metabolized (e.g. dehydroxylated) by gut microbiota to secondary BAs, which can still be passively absorbed as unconjugated BAs in the colon. Unconjugated BAs are partially reconjugated (and rehydroxylated) during their passage through the liver before being excreted into bile again, which completes their enterohepatic cycle. In addition, BAs are filtered by the glomeruli and then reabsorbed in renal tubules, again limiting their renal loss.
BAs may also cycle between cholangiocytes and hepatocytes through a cholehepatic shunt pathway. Unconjugated BAs induce a greater degree of bile flow per BA molecule excreted in bile. To account for this hypercholeretic effect, it was proposed that unconjugated BAs may be passively absorbed by bile ducts, enter the peribiliary plexus adjacent to intrahepatic bile ducts, and then forwarded to the hepatic sinusoids to be returned to cholangiocytes by hepatocyte secretion. Cholehepatic shunting initiated by passive absorption of non‐ionized bile salt results in the generation of HCO3–‐rich hypercholeresis [4,5].
Figure 1.2 Enterohepatic circulation of bile acids (BAs). After hepatic synthesis and biliary secretion, BAs undergo enterohepatic circulation. The BSEP (ABCB11) is the main canalicular transporter for BAs. After reabsorbtion by ASBT/SLC10A1 in the ileum, BAs (and exit through OSTα/β from enterocytes; not shown) are transported back to the liver through the portal blood. Reuptake of conjugated BA from portal blood through NTCP/SLC10A1 (and OATPs for unconjugated BAs; not shown) into the hepatocytes completes the enterohepatic circulation. ASBT, apical sodium‐dependent bile salt transporter; BSEP, bile salt export pump; NTCP, sodium taurocholate cotransporting polypeptide; OATPs, organic anion transporters; OST, organic solute transporter α/β.
Source: Trauner et al. [5]. Reproduced with permission of John Wiley and Sons.
Death and Regeneration of Hepatocytes
Cell Death
Hepatocytes can die because of either necrosis or apoptosis. Necrosis is the loss of plasma membrane integrity with release of the cellular contents locally, which triggers an inflammatory response. Apoptosis is a highly regulated process in which cells that are damaged, senescent or deregulated self‐destruct with a lower release of inflammatory products. Dying cells undergo morphologic modifications including chromatin condensation, nuclear fragmentation, and generation of apoptotic bodies. Furthermore, they express signals on the cell surface that allow macrophage recognition. Apoptosis is essential to avoid the outflow of intracellular contents and to limit the immunologic response against intracellular autoantigens. Nevertheless, apoptotic bodies and fragments can under some circumstances constitute a major source of immunogens in autoimmune diseases that involve the targeting of ubiquitous autoantigens. This has been described in PBC. In the BECs of patients with PBC there is increased DNA fragmentation, implying increased apoptosis, when compared with normal controls. While mitochondrial proteins are present in all nucleated cells, in PBC there is a highly specific multilineage immune response directed to the nominal mitochondrial autoantigenic epitope, the inner lipoyl domain of the E2 subunit of the pyruvate dehydrogenase complex (PDC‐E2) of the BECs. Apoptosis of BECs has been proposed as a potential source of “neoantigens” that could be responsible for activation of autoreactive T lymphocytes or a target for effector cells or antibodies. PDC‐E2 is not only immunologically intact during apoptosis in BECs, but it localizes in the apoptotic bodies of BECs where it is accessible to recognition by anti‐mitochondrial antibodies.
Liver Regeneration
Liver possesses a unique capacity to replace its mass after tissue injury or loss. The regenerative process involves a cascade of events that moves cells from their resting G0 phase through G1, S phase (DNA synthesis), and G2 to M phase (mitotic cell division). A typical example is hepatic growth after partial hepatectomy. The majority of research on liver regeneration has focused on cytokine‐ and growth factor‐ mediated pathways involved in initiation and progression through the cell cycle. During more extensive acute liver injury, which far exceeds the capacity of remaining healthy hepatocytes to replicate and restore liver function, resident liver progenitor cells (i.e. oval cells) are activated to support or take over the role of regeneration. In adults, there are multiple niches of biliary tree stem/progenitor cells (BTSCs) residing in different locations along the human biliary tree and niches found within the liver parenchyma, with a key role in regeneration of the liver. Figure 1.3 shows the location of stem/progenitor cell niches in the human biliary tree. Canals of Hering harbor hepatic stem/progenitor cells (HpSCs), while peribiliary glands (PBGs) constitute the niche for BTSCs.
Figure 1.3 Stem/progenitor cell niches in the human biliary tree. Canals of Hering harbor hepatic stem/progenitor cells (HpSCs), while peribiliary glands (PBGs) constitute the niche for biliary tree stem/progenitor cells (BTSCs). ASH, alcoholic steatohepatitis; BA, bile acid; CCA, cholangiocarcinoma; NAFLD, non‐alcoholic fatty liver disease; NAS, non‐anastomotic strictures; PSC, primary sclerosing cholangitis.
Source: Overi et al. [6].
Those within the biliary tree are found in PBGs and contain especially primitive stem cell populations, expressing endodermal transcription factors relevant to both liver and pancreas, pluripotency genes, and even markers indicating a genetic signature overlapping with that of intestinal stem cells [7]. The distribution of PBGs is not uniform, varying along the biliary tree: PBGs are mostly found in the hepatopancreatic ampulla and are less numerous in the common bile duct; they are not present in the gallbladder, but a stem cell‐like compartment is located in the epithelial crypts. Biliary progenitors support the renewal of large intrahepatic and extrahepatic bile ducts. Stem cells are present in the canals of Hering, and participate
