Characterizing the Role of HMG-CoA Reductase in Aryl Hydrocarbon Receptor-Mediated Liver Injury in C57BL/6 Mice

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.

Characterizing the impact of simvastatin co-treatment of cell specific TCDD-induced gene expression and systemic toxicity

“…Previously, we characterized the impact of HMGCR repression in TCDD-induced liver injury by co-treating mice with TCDD and simvastatin, a commonly prescribed HMCGR competitive inhibitor. In that study, co-treatment decreased TCDD-mediated hepatic lipid accumulation in males and females, increased glycogen and decreased ketone bodies in female mice and increased alanine aminotransferase levels in male mice, suggesting statins alter TCDD-induced changes to metabolism and these changes might play a role in toxicant-induced injury 12 . As millions of people take statins, it is important to elucidate the additional risk statins present to populations exposed to TCDD and related compounds 21 .…”

“…One major pathway that is impacted by TCDD is cholesterol biosynthesis by suppressing the expression of genes that encode key enzymes in the process, including the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) 10 – 12 . These expression changes correlate with an alteration in circulating free cholesterol levels, high-density lipoproteins (HDLs) and low-density lipoproteins (LDLs) in mice 10 – 12 .…”

“…One major pathway that is impacted by TCDD is cholesterol biosynthesis by suppressing the expression of genes that encode key enzymes in the process, including the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) 10 – 12 . These expression changes correlate with an alteration in circulating free cholesterol levels, high-density lipoproteins (HDLs) and low-density lipoproteins (LDLs) in mice 10 – 12 . Dysregulation of cholesterol homeostasis is one of the conditions that can lead to the development of metabolic syndrome (MetS), and TCDD exposure is associated with an increased incidence of MetS in humans 13 – 15 .…”

Dose-dependent disruption of hepatic zonation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice: integration of single-nuclei RNA sequencing and spatial transcriptomics

“…Enrichment of lysosomal related genes in macrophages is consistent with lysosomes contributing to the internalization of cholesterol in Kupffer cells (KCs) driven in part by Cd36 (Bieghs et al , 2012). Cd36 is a direct target of TCDD activated AHR that leads to cholesterol and cholesterol ester accumulation in the liver (Dornbos et al , 2019; Lee et al , 2010; Nault et al , 2017b). Foamlike KCs secrete chemokines that recruit other immune cell types including neutrophils in addition to the recruitment by leukotrienes induced by TCDD (Doskey et al , 2020; Takeda et al , 2017).…”

Emerging concepts and opportunities for endocrine disruptor screening of the non-EATS modalities

“…In addition, other studies demonstrate that inhibition of AHR by the AHR antagonist α-naphthoflavone prevents obesity and fatty liver in male and female mice ( Moyer et al, 2017 ; Rojas et al, 2020 ). On the contrary, AHR activation in rodents by environmental contaminants is associated with spontaneous hepatic steatosis characterized by the accumulation of triglycerides ( Dong et al, 2019 ; Lee et al, 2010 ; Nebert, 2017 ), cholesterol biosynthesis impairments ( Dornbos et al, 2019 ; Sato et al, 2008 ; Zhu et al, 2019 ) and systemic metabolic dysfunction ( Zhang et al, 2015 ). The effects of AHR ligand like dioxin on lipogenesis appear to be concentration dependent and non-monotonous like other effects of endocrine disruptors ( Baker et al, 2015 ).…”