Characterizing the Role of HMG-CoA Reductase in Aryl Hydrocarbon Receptor-Mediated Liver Injury in C57BL/6 Mice
| Autor: | Peter Dornbos, John J. LaPres, Kelly A. Fader, Kurt J. Williams, Amanda Jurgelewicz, Timothy R. Zacharewski |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Polychlorinated Dibenzodioxins Molecular biology lcsh:Medicine 010501 environmental sciences Reductase 01 natural sciences Biochemistry Article 03 medical and health sciences Mice Internal medicine medicine Animals lcsh:Science Receptor 0105 earth and related environmental sciences Liver injury Multidisciplinary biology Chemistry lcsh:R Fatty liver medicine.disease Aryl hydrocarbon receptor 3. Good health Mice Inbred C57BL 030104 developmental biology Endocrinology Liver Receptors Aryl Hydrocarbon Simvastatin HMG-CoA reductase biology.protein lcsh:Q lipids (amino acids peptides and proteins) Female Hydroxymethylglutaryl CoA Reductases Steatosis medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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