Superfund Research Program

Effect of Underlying Liver Diseases on Fibrosis Induced by Superfund Toxicants

Project Leader: David A. Brenner
Grant Number: P42ES010337
Funding Period: 2011-2017

Project-Specific Links

Final Progress Reports

Year:   2016 

The research team continues to investigate the underlying molecular mechanisms of superfund toxicant-induced liver damage and liver fibrosis. In this project, researchers use carbon tetrachloride (CCl4), a superfund toxicant. Acute CCl4 exposure induces severe hepatocyte damage. Chronic CCl4 exposure will cause liver fibrosis through activation of hepatic stellate cells (HSCs). Acute CCl4 exposure significantly altered pathways of estrogen biosynthesis, LXR/RXR, FXR/RXR, PXR/RXR, xenobiotic metabolism, aryl hydrocarbon receptor, bile acid biosynthesis and beta-oxidation pathways, as demonstrated through the proteomics analysis. The data also showed CCl4 exposure reduced the expression of mitochondria-related proteins and the activity of electron transport chain-reaction through proteomics and Seahorse bioanalyzer, respectively, suggesting that CCl4 exposure is associated with mitochondria damage. Accumulation of damaged mitochondria produces more reactive oxygen species (ROS) from hepatocytes, which is an underlying mechanism of HSC activation and liver fibrosis.

Ubiquitination of mitochondrial proteins is a post-translational modification to maintain mitochondrial function and turnover, most likely, through mitophagy, a form of autophagy for mitochondria. Researchers found that CCl4 exposure translocated Ubc13, an E2 ubiquitin ligase, to mitochondria and that Ubc13 can modulate ubiquitination of mitochondrial proteins in hepatocytes. The researchers examined the role of hepatocyte Ubc13 in vivo by generating hepatocyte-specific Ubc13-deficient (Ubc13KO) mice. Upon CCl4 exposure, Ubc13KO mice had exacerbated liver injury and fibrosis. It was previously reported that a fatty liver condition enhances toxin-induced liver fibrosis. In advanced fatty liver disease, hepatic Ubc13 levels were reduced, which may be an underlying mechanism of enhanced toxin-induced liver fibrosis in a fatty liver condition.