Mechanisms of oxysterol-induced disease: insights from the biliary system

Abstract

Oxysterols are oxidized species of cholesterol that are derived from exogenous (e.g. dietary) and endogenous (in vivo) sources. Oxysterols play critical roles in normal physiologic functions as well as in pathophysiologic processes in a variety of organ systems. This review provides an overview of oxysterol biology from the vantage point of the biliary system. Several oxysterols have been identified in human bile in the context of biliary tract infection and inflammation. This finding has led to investigations regarding the potential pathophysiologic significance of biliary oxysterols in diseases affecting the biliary system, with an emphasis on cholangiocarcinoma. Emerging evidence implicates specific oxysterols in the development and progression of this malignancy. This review will summarize the literature on oxysterols in the biliary system and discuss how the accumulated evidence contributes to a hypothesis describing the molecular basis of cholangiocarcinogenesis.

Keywords: Opisthorchis viverrini; bile; bile acids; biliary tract; cholangiocarcinoma; cholangiocytes; cholesterol; gallbladder; gallstones; oxysterols.

Figure 1. Cholesterol and several common oxysterols

(A) Oxysterols derived from oxidation in one of the sterol rings; (B) oxysterols derived from side-chain oxidation. Adapted from [1] with permission.

Figure 2. A conceptual framework for the role of biliary oxysterols in biliary tract diseases

Chronic or recurrent biliary tract infection, as represented by recurrent pyogenic cholangitis, bacterial colonization in gallstones and Opisthorchis viverrini infection, induces inflammation. This chronic inflammatory state is associated with activated leukocytes, which produce ROS mediated by NADPH oxidase and via the induction of proinflammatory cytokines such as IL-1 and IL-6. The resultant pro-oxidative milieu, represented by the relative overabundance of ROS/RNS induces the production of various oxysterol species through oxidation of biliary cholesterol. Biliary epithelial cells that are chronically exposed to these oxysterol species undergo apoptosis, DNA damage and repair, and altered mucin secretion. These physiologic effects are modulated by the bile acid milieu, perhaps through FXR- and TGR5-mediated mechanisms. Over time, a pathophysiologic response develops through failure of apoptosis and/or defective DNA repair, allowing a clone of resistant cells to undergo neoplastic change. Altered mucin secretion can also induce changes in the biliary milieu to favor gallstone formation. ROS: Reactive oxygen species; RNS: Reactive nitrogen species.