1. Figure 3 Bile acid-induced hepatic inflammation and carcinogenesis
Figure 3 | Bile acid-induced hepatic inflammation and carcinogenesis. Due to their lipophilic, detergent properties, bile acids (BAs) can directly disrupt the plasma membrane and cause activation of protein kinase C (PKC), which then activates the p38 mitogen-activated protein kinase (p38 MAPK) pathway. The resultant activation of p53 and nuclear factor kappa-B (NF-κB) lead to the induction of apoptosis and increased inflammation. Activated NF-κB translocates to the nucleus and promotes the transcription of genes that encode pro-inflammatory cytokines such as TNF, IL-1β and IL-6, which can positively regulate NF-κB activation and thus promote a continued cycle of inflammation. IL-6 also activates the Janus kinase (JAK)–signal transducer and activator of transcription 3 (STAT3) pathway, which leads to decreased apoptosis and the progression of hepatocellular carcinoma (HCC)101. IL-1β also activates the phosphoinositide 3-kinase (PI3K)– MDM2 pathway to negatively regulate p53, thus increasing the survival of DNA-damaged cells through reduced apoptosis, which might lead to HCC102. The NF-κB p65 subunit has also been shown to bind directly to farnesoid X receptor (FXR) and inhibit its transcriptional activity, resulting in reduced expression of bile acid transporters (such as organic solute transporter subunit α (OSTα), OSTβ, bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), multidrug resistance protein (MDR2) and MDR3), which leads to decreased bile acid efflux and cholestasis and increased biosynthesis of bile acids84. Inhibition of FXR transcription collectively leads to increased levels of bile acids in the liver,which causes inflammation that can lead to HCC. Membrane perturbation by bile acids can also activate phospholipase A2 (PLA2), causing the release of arachidonic acid (AA) from the cell membrane, which can be metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) to generate reactive oxygen species (ROS) in hepatocytes and, consequently, induce DNA damage103,104. ROS can directly activate NF-κB and can also induce direct DNA damage in cells, which might lead to HCC105.
Jia, W. et al. (2017) Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis
Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro