Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.


The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Your Environment. Your Health.

Progress Reports: Michigan State University: TCDD-Elicited Steatosis: The Role of Aryl Hydrocarbon Receptor Regulation in Lipid Uptake, Metabolism, and Transport

Superfund Research Program

TCDD-Elicited Steatosis: The Role of Aryl Hydrocarbon Receptor Regulation in Lipid Uptake, Metabolism, and Transport

Project Leader: Timothy R. Zacharewski
Grant Number: P42ES004911
Funding Period: 2006-2021
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

Learn More About the Grantee

Visit the grantee's eNewsletter page Visit the grantee's eNewsletter page

Progress Reports

Year:   2020  2019  2018  2017  2016  2015  2014  2012  2011  2010  2009  2008  2007  2006 

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds play an underappreciated role in non-alcoholic fatty liver disease (NAFLD). Through the investigation of metabolic pathways, the research team shows that TCDD elicits widespread metabolic reprogramming. The team demonstrates that TCDD alters the SAM/SAH ratio and one carbon metabolism (OCM) through changes in gene expression that may be secondary to initial AhR activation (Fling 2019). Along with OCM dysregulation was the alteration of protein levels for genes involved in transsulfuration pathways including a >900-fold increase in the cystine/glutamate transporter Slc7a11, leading to decreased production of hepatic H2S. Shotgun metagenomics revealed widespread changes in the gut microbiome highlighted by a decrease in the Bacteroides/Firmicutes ratio and an increase in species expressing the bile salt hydrolases with implications for fermentation. Metabolomic analysis of acyl-CoA species further identified the repression of enzymes involved in beta-oxidation, particularly enoyl-CoA hydratase 1 (ECHS1), leading to incomplete oxidation and a futile cycle of free fatty acid activation↔acyl-CoA hydrolysis (Cholico 2021). The integration of disparate omic technologies also identified metabolic reprogramming associated with the increased production of the toxic metabolite acryl-CoA due to cobalamin (Cbl) depletion and redirecting propionyl-CoA to the non-canonical Cbl-independent beta-oxidation-like pathway. ChIP-seq and single-nuclei RNA sequencing (snRNAseq) (Nault 2020) further elucidated the mechanism of TCDD induced NAFLD pathogenesis and demonstrated that data from snRNAseq analysis of frozen tissue was comparable to single cell RNA sequencing analysis of fresh tissue. Collectively, TCDD elicited significant metabolic reprogramming leading to use of alternative pathways within distinct hepatic and immunological cell types resulting in hepatotoxicity and NAFLD-like pathologies including the progression of steatosis to steatohepatitis with fibrosis.

to Top