Hepatocellular carcinoma: Novel understandings and therapeutic strategies based on bile acids (Review)

Abstract

Bile acids (BAs) are the major components of bile and products of cholesterol metabolism. Cholesterol is catalyzed by a variety of enzymes in the liver to form primary BAs, which are excreted into the intestine with bile, and secondary BAs are formed under the modification of the gut microbiota. Most of the BAs return to the liver via the portal vein, completing the process of enterohepatic circulation. BAs have an important role in the development of hepatocellular carcinoma (HCC), which may participate in the progression of HCC by recognizing receptors such as farnesoid X receptor (FXR) and mediating multiple downstream pathways. Certain BAs, such as ursodeoxycholic acid and obeticholic acid, were indicated to be able to delay liver injury and HCC progression. In the present review, the structure and function of BAs were introduced and the metabolism of BAs and the process of enterohepatic circulation were outlined. Furthermore, the mechanisms by which BAs participate in the development of HCC were summarized and possible strategies for targeting BAs and key sites of their metabolic processes to treat HCC were suggested.

Keywords: bile acid; enterohepatic circulation; farnesoid x receptor; hepatocellular carcinoma; obeticholic acid; ursodeoxycholic acid.

Figure 1

Structure of cholesterol and bile acids [refs. (6-8)]. CA, cholic acid; UDCA, ursodeoxycholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; MCA, muricholic acid.

Figure 2

Processes of BA synthesis. In the liver, the classical pathway is initiated by CYP7A1, the rate-limiting enzyme. CYP7A1 and HSD3B7 are able to convert cholesterol to form C4. CYP8B1 performs 12α-hydroxylation of C4. Subsequently, under the catalysis of AKR1D1, AKR1C4 and CYP27A1, THCA is generated. However, without 12α-hydroxylation, C4 is converted to DHCA. BACS or VLCS in the ER then ligate Co-A to the carboxyl groups. After transport by peroxisomal transporter ABCD3 and catalysis by a series of enzymes, THCA and DHCA synthesize cholyl-CoA and chenodeoxycholyl-CoA. These two substances are then conjugated to taurine or glycine by BAAT. The alternative pathway is mainly initiated by CYP27A1. Next, through CYP7B1 and other enzymes that belong to CYP proteins, cholesterol is being subjected to modifications to finally generate CDCA and a small amount of CA. Certain conjugated forms of BAs entering the intestine may be dissociated by BSH and bacterial 7α dehydroxylase may then convert CA and CDCA into DCA and LCA, respectively. CDCA may also be isomerized to UDCA. In mice, the generation of MCA was observed in addition to the above synthetic processes [Refs. (6-8,12)]. BA, bile acid; BSH, BA hydrolase; HSD3B7, 3β-hydroxy-5-C27-steroid dehydrogenase; C4, 7α-hydroxy-4-cholesten-3-one; CYP, cytochrome P450; CYP8B1, sterol 12α-hydroxylase; CYP7B1, nonspecific oxysterol 7α-hydroxylase; AKR1D1, aldo-keto reductase family 1 member D1; BAAT, BA-CoA:amino acid N-acyltransferase; THCA, 3α,7α,12α-trihydroxy-5β cholestanoic acid; DHCA, 3α,7α-dihydroxy-5β cholestanoic acid; BACS, BA-Co-A synthase; VLCS, very long-chain Co-A synthase; ER, endoplasmic reticulum; CA, cholic acid; CDCA, chenodeoxycholic acid; UDCA, ursodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; MCA, muricholic acid; ABCD3, ATP binding cassette subfamily D member 3.

Figure 3

Enterohepatic circulation of BAs. BA, bile acid; BSEP, bile salt export pump; MRP2, multidrug resistance-associated protein 2; ASBT, apical sodium-dependent BA transporter; IBABP, intestinal BA binding protein; OST, organic solute transporter; NTCP, sodium-taurocholate co-transporting polypeptide; OATP, organic anion transporting polypeptide.

Figure 4

Intracellular signaling in HCC mediated by FXR and TGR5. BA, bile acid; HCC, hepatocellular carcinoma; EMT, epithelial to mesenchymal transition; FXR, FXR, farnesoid X receptor; SOCS3, suppressor of cytokine signaling 3; TGR5, Takeda G protein-coupled receptor 5; miR, microRNA; FGFR, fibroblast growth factor receptor; NDRG2, N-myc downstream-regulated gene 2; α7-nAChR, α7-nicotinic acetylcholine receptor.

Figure 5

Mechanisms involved in BA-mediated hepatocarcinogenesis. BA, bile acid; HCC, hepatocellular carcinoma; FXR, FXR, farnesoid X receptor; TGR5, Takeda G protein-coupled receptor 5; ROS, reactive oxygen species; MAFG, MAF bZIP transcription factor G; YAP, Yes-associated protein; p110γ, PI3K class I isoforms γ; PKC, protein kinase C; LSEC, liver sinusoidal endothelial cell; CXCR, C-X-C motif chemokine receptor type; HSC, hepatic stellate cell; NKT, natural killer T; SASP, senescence-associated secretory phenotype.