Bile acid-mediated signaling in cholestatic liver diseases

Abstract

Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease.

MAPL loss dysregulates bile and liver metabolism in mice

“…For example, primary C24 beta‐muricholic (b‐MCA) bile acid was increased from ~10,000 to 30,000 fmol/g of liver tissue, and from 600 to 3,500 nM in MAPL −/− serum (Fig 2C, Table EV2). In contrast, both precursors and conjugated bile acids were decreased by more than 50% in feces (Fig 2C, Table EV2), suggestive of bile flow stalling through the liver/gallbladder biliary system (cholestasis, typically resulting in tissue damage) or increased reabsorption from the gut into circulation (Zeng et al , 2023). Histological examination of liver and damage markers showed no evidence of cholestasis, as morphology of bile canaliculi was normal, no signs of necrosis were present and serum alanine transaminase/aspartate aminotransferase (ALT/AST) were not changed (Figs 2C–E and EV2B).…”

“…Bile acids are physiological detergents whose levels are controlled by a balance of enzymes involved in biosynthesis and detoxification, where regulation is responsive to both feedback and feed‐forward mechanisms (Zeng et al , 2023). As MAPL −/− mice showed elevated hepatic bile acid production at fed state, but no liver damage or increased bile acid elimination, we explored in detail the multi‐layered regulation of the pathway within the liver.…”

Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR

“… 18 , 19 MBSCs likely act as ligands for host bile salt receptors, including farnesoid X receptor (FXR) and pregnane X receptor, and accordingly have the potential to modulate processes controlled by these nuclear receptors. 18 , 20 A recent study demonstrated that several MBSCs inhibit the germination of Clostridium difficile spores in vitro, pointing toward the a role of MBSCs in bacterial communication. 14 Analysis of public mass spectrometry datasets revealed an association between fecal MBSC abundance ( viz.…”

Quantitative proteomics reveals the protective effects of Yinchenzhufu decoction against cholestatic liver fibrosis in mice by inhibiting the PDGFRβ/PI3K/AKT pathway

“…CLD is associated with the accumulation of bile acids (BAs) in the liver, resulting in liver inflammation, hepatocyte damage, and liver fibrosis and cirrhosis, for which treatment options are limited ( Goodman, 2007 ; Gines et al, 2021 ). Persistent cholestasis may lead to chronic inflammatory responses within the liver and damage bile duct cells and hepatocytes ( Cai et al, 2017 ; Zeng et al, 2023 ). Various factors associated with hepatocyte apoptosis and necrosis, including inflammation in the liver and activation of Kupffer cells, trigger the secretion of pro-inflammatory cytokines ( Kisseleva and Brenner, 2021 ).…”