Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 19 (3), 215-228

Inflammation and Cell Death During Cholestasis: The Evolving Role of Bile Acids

Affiliations

Inflammation and Cell Death During Cholestasis: The Evolving Role of Bile Acids

Benjamin L Woolbright et al. Gene Expr.

Abstract

Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis. Despite this, a surge of papers in the last decade have reported a primary role for inflammation in the pathophysiology of cholestatic liver injury. Furthermore, it has increasingly been recognized that both the constituency of individual bile acids that make up the greater pool, as well as their conjugation status, is intimately involved in their toxicity, and this varies between species. Finally, the role of bile acids in drug-induced cholestatic liver injury remains an area of increasing interest. The purpose of this review is to critically evaluate current proposed mechanisms of cholestatic liver injury, with a focus on the evolving role of bile acids in cell death and inflammation.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Bile acid synthesis. Bile acids are synthesized from cholesterol by cytochrome p450s (CYP) to either cholic acid (CA) or chenodeoxycholic acid (CDCA). Dehydroxylation by gut bacteria results in lithocholic acid (LCA) or deoxycholic acid (DCA). Conjugation of CA or CDCA to taurine/glycine results in taurochenodeoxycholic/taurocholic acid (TCDCA/TCA) or glycochenodeoxycholic/glycocholic acid (GCA/GCDCA). Dehydroxylated bile acids can also be conjugated to taurine/glycine. Dehydrox., dehydroxylated.
Figure 2
Figure 2
Serum bile acid levels in human patients with or without cholestasis. Serum bile acids were measured in healthy or cholestatic patients (A), or healthy or patients with primary sclerosing cholangitis (B), or healthy or cholestatic patients with mixed etiology of cholestasis (C). Data adapted from References , . BA, bile acid.
Figure 3
Figure 3
Bile duct ligation histology. H&E stain of a mouse liver 24 h post-bile duct ligation. Blue arrows represent inflammatory cells. Red arrows represent areas of feathery necrosis inside the infarct. Green arrows on the 100× images represent obvious areas of infarction and cell death.
Figure 4
Figure 4
Proposed model of neutrophil-induced injury. Infarction of the biliary tract results in hepatocyte damage and release of bile acids (BA) and damage-associated molecular patterns (DAMPs). This releases cytokines like CXC-ligands 1 and 2 or IL-17 and increased early growth factor response-1 activity. Neutrophils (PMN) recognize these signals and adhere firmly to hepatocytes via CD18/intercellular adhesion molecule-1 (ICAM-1) and induce cell death through ROS production.
Figure 5
Figure 5
Proposed model of bile acid inflammatory signaling. Bile acids activate an unknown receptor, potentially sphingosine 1 phosphate receptor 2 (S1PR2) or G-protein-coupled bile acid receptor (TGR5), to initiate mitogen-activated protein kinase and c-Jun N-terminal kinase pathways. These increase early growth factor response-1 (Egr1) activity and induce proinflammatory gene induction.

Similar articles

See all similar articles

Cited by 1 PubMed Central articles

Publication types

LinkOut - more resources

Feedback