Chronic liver injury has long been associated with progressive liver disease toward the development of steatohepatitis and the subsequent increased risk of hepatocellular carcinoma (HCC). Altered bile acid (BA) metabolism has also been associated closely with liver injury. However, the mechanistic role of BAs in hepatic pathogenesis has, so far, remained unclear. Intracellular accumulation of hydrophobic BAs such as deoxycholic acid (DCA), lithocholic acid (LCA), and taurodeoxycholic acid (TDCA), which appear to be the most cytotoxic species among BAs, has been proposed as a mechanism of cholestatic liver injury. These gut microbe - metabolized compounds, when accumulated in hepatocytes, result in mitochondrial damage, disruption of cell membranes, and production of reactive oxygen species, ultimately leading to apoptosis or necrosis. In this study, we hypothesize that gut microbiota mediated intrahepatic accumulation of BAs critically mediates sustained hepatocellular injury responsible for the subsequent development of fibrosis and malignancy. The project is also intended to provide direct evidence to demonstrate the efficacy of regulating BA metabolism as a treatment for liver injury, protecting against the development of cirrhosis and cancer.
Four Specific Aims are designed to test the above hypothesis.
The Aim 1 of the project is to determine the impact of gut microbiome on host BA profiles. Mouse models and cell lines will be used to address two questions: (1) what is the role of gut microbiome in mediating hepatic and peripheral BA alteration? (2) how do gut microbiota and hepatic BA profile change as steatohepatitis progresses from fatty liver to HCC? The Aim 2 of the project is to determine the role of BAs in FXR regulation in liver injury and carcinogenesis. In vitro models as well as a FXR-knock-out mouse model will be used to address the following questions, (1) how do BAs impact the production of proinflammatory cytokines, (2) can BAs induce malignant transformation of normal liver cell in vitro? (3) can altered BAs influence functions of hepatic BA transporters, and (4) how does hepatic FXR-bile acid interaction impact BA transporters, drug retention, and liver injury? The Aim 3 is to establish a statistical correlation between gut microbiome and host BA metabolome.
The Aim 4 is to explore the molecular mechanisms of hepatic toxicity of BAs and the ameliorative effect of BA homeostasis therapies.
Alterations in gut bacteria may result in an increase in the concentration of toxic bile acids in liver, causing sustained liver injury and the subsequent development of liver fibrosis and cancer. The proposed study will help us design novel therapeutic approaches to protect against the development of liver cancer.
