Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. The prototypical ligand of the AHR is an environmental contaminant called 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure is associated with many adverse health outcomes in humans including non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that AHR ligands alter cholesterol homeostasis in mice through repression of genes involved in cholesterol biosynthesis, such as Hmgcr, which encodes the rate-limiting enzyme of cholesterol biosynthesis called 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR). In this study, we sought to characterize the impact of HMGCR repression in TCDD-induced liver injury. C57BL/6 mice were exposed to TCDD in the presence or absence of simvastatin, a competitive inhibitor of HMGCR. Simvastatin exposure decreased TCDD-induced hepatic lipid accumulation in both sexes, but was most prominent in females. Simvastatin and TCDD (S + T) co-treatment increased hepatic AHR-battery gene expression and liver injury in male, but not female, mice. In addition, the S + T co-treatment led to an increase in hepatic glycogen content that coincides with heavier liver in female mice. Results from this study suggest that statins, which are amongst the most prescribed pharmaceuticals, may protect from AHR-mediated steatosis, but alter glycogen metabolism and increase the risk of TCDD-elicited liver damage in a sex-specific manner.
Highlights
In humans, TCDD exposure is associated with a plethora of adverse health outcomes, such as chloracne, immunosuppression, and cancer[12,13,14,15]
Mice of both sexes that were co-treated with S + T were observed to have an overall increased level of expression in genes involved in cholesterol biosynthesis as compared to TCDD alone; expression of Dhcr[7], squalene epoxidase (Sqle), and Cyp[51] were significantly increased as compared to TCDD alone in females while Dhcr[7] and Sqle was significantly increased in males
Previous in vitro- and rodent-based studies have indicated that exposures to aryl hydrocarbon receptor (AHR) ligands repress expression of genes involved in cholesterol biosynthesis and lead to reductions of serum total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) in serum[22,23]
Summary
TCDD exposure is associated with a plethora of adverse health outcomes, such as chloracne, immunosuppression, and cancer[12,13,14,15]. TCDD treatment leads to accumulation of lipids in the liver that can progress to steatohepatitis with fibrosis[18,19,20,21]. Further studies have shown that, while hepatic cholesterol biosynthesis www.nature.com/scientificreports is repressed, repeated TCDD treatment leads to increased hepatic cholesterol ester (CE) content in mice which is possibly due to repression of VLDL secretion and decreased bile acid synthesis and secretion[18,24]. Given the complex regulation of cholesterol biosynthesis and its importance to organismal health, we sought to better-characterize the impact of HMGCR repression in TCDD-induced liver injury. Our results indicate that HMGCR activity likely plays a key, but sex-specific, role in TCDD-elicited liver injury. This study suggests that statins used to control hypercholesterolemia may increase the risk of sex-specific liver injury from exposure to AHR ligands, such as TCDD
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