Bile acids and their receptors: modulators and therapeutic targets in liver inflammation

Abstract

Bile acids participate in the intestinal emulsion, digestion, and absorption of lipids and fat-soluble vitamins. When present in high concentrations, as in cholestatic liver diseases, bile acids can damage cells and cause inflammation. After the discovery of bile acids receptors about two decades ago, bile acids are considered signaling molecules. Besides regulating bile acid, xenobiotic, and nutrient metabolism, bile acids and their receptors have shown immunomodulatory properties and have been proposed as therapeutic targets for inflammatory diseases of the liver. This review focuses on bile acid-related signaling pathways that affect inflammation in the liver and provides an overview of the preclinical and clinical applications of modulators of these pathways for the treatment of cholestatic and autoimmune liver diseases.

Keywords: Bile acid receptors; Bile acids; Cholestasis; FXR; Inflammation; Liver; TGR5.

Fig. 1

Bile acid homeostasis and bile acid–related treatments in cholestatic liver diseases. Bile acids are synthesized by hepatocytes in the liver from cholesterol and secreted into bile. After being modified by the bile duct epithelium, the bile is secreted in the duodenum to accomplish digestive functions. Under the action of the intestinal microbiota, primary bile acids are modified into secondary bile acids. Bile acids are in large part re-absorbed by ileal ASBT to be returned to the liver via the portal circulation. Upon intestinal reabsorption, bile acids activate FXR-FGF19 that negatively regulates bile acids synthesis in the liver. The different steps of the enterohepatic circulation can potentially be targeted in cholestatic liver diseases to antagonize the effects of bile acids accumulation. In the figure are reported selected drugs that are in experimental trial or approved for (1) interrupting the enterohepatic circulation, (2) reducing bile acids uptake, (3) reducing bile acids synthesis, (4) increasing bile flow and decreasing bile acid hydrophobicity. ASBT: apical sodium–dependent bile acid transporter; BAs: bile acids; FXR: farnesoid X receptor; FGF19: fibroblast growth factor 19; nor-UDCA: nor-ursodeoxycholic acid; NTCP: Na⁺-dependent taurocholate cotransporting peptide; UDCA: ursodeoxycholic acid

Fig. 2

Effects of bile acid accumulation in the liver. Bile acid accumulation in cholestatic conditions can activate different signaling pathways in different cell types of the liver. Damaged hepatocytes can initiate an inflammatory response by secreting chemokines and DAMPs that activate other cells (i.e., cholangiocytes, HSCs, and inflammatory cells). High levels of bile acids can also directly disrupt tight junctions and basal membrane of bile ducts, leading to activation of cholangiocytes and perpetuation of the inflammatory/fibrotic response with proliferation and activation of HSCs. Persistent chronic inflammation and fibrosis can progress into cirrhosis. DAMPs: damage-associated molecular patterns; HSCs: hepatic stellate cells; lncRNA H19: long non-coding RNA H19

Fig. 3

Effect of FXR activation on liver inflammation. Activation arrows are indicated in black and inhibition arrows in red. AP-1: activator protein 1; CA: cholic acid; CDCA: chenodeoxycholic acid; CYP450: cytochrome P450 family 7 subfamily A member 1; DCA: deoxycholic acid; FGF19: fibroblast growth factor 19; FXR: farnesoid X receptor; LCA: lithocholic acid; MDSCs: myeloid-derived suppressor cells; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NOD-, LRR- and pyrin domain–containing protein 3; SHP: small heterodimer partner; SOCS3: suppressor of cytokine signaling 3

Fig. 4

Effect of TGR5 activation on liver inflammation. Activation arrows are indicated in black and inhibition arrows in red. AKT-mTOR: protein kinase B—mammalian target of rapamycin signaling pathway; CA: cholic acid; CDCA: chenodeoxycholic acid; DCA: deoxycholic acid; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; LCA: lithocholic acid; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NOD-, LRR- and pyrin domain–containing protein 3; TGR5: takeda-G-protein-receptor-5