Graduate Thesis Or Dissertation
 

Alteration of cholesterol disposition by chlordecone is not explained by induction of cyp7a or cyp4a1

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  • Liver X receptor (LXR), farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) are adopted orphan nuclear receptors that function as lipid sensors. These receptors respond to cellular lipid levels and regulate the expression of target gene. Previously, it was demonstrated that low doses of chlordecone (CD) pretreatment disturbed exogenous cholesterol distribution and cellular lipid transport, storage and metabolism pathway. The aim of this study was to determine whether low doses of CD affect nuclear receptor (LXRα/FXR or PPARα)-mediated lipid homeostasis. Thus, hepatic microsomal protein contents of cytochrome P450 7a (cyp7a, regulated by LXRα/FXR), and P450 4a1 (cyp4a1, regulated by PPARα) were determined in male C57BL/6N mice, fed AIN76 or AIN93M diet, received CD (2.5, 5.0 or 15 mg CD/kg body weight). Western blot analysis was used for protein measurements using appropriate antibodies. Cyp7a and cyp4a1 protein levels were confirmed by enzyme activities, cholesterol 7α-hydroxylase and lauric acid hydroxylase activities, respectively. Plasma total cholesterol and triglycerides, body and liver weights were also measured in these dose-response experiments. Plasma total cholesterol and triglycerides levels from animals fed AIN 93M diet were significantly lower than those from animals fed AN 76 diet. However, neither total plasma cholesterol nor triglycerides levels were changed in CD-treated mice fed AN 76 or AN 93M diet. Cyp7a protein level or its enzyme activity was not altered by CD treatment. Likewise, cyp4a1 protein level or its activity was not affected by CD treatment. In summary, the results of the present study do not support the hypothesis that CD treatment alters nuclear receptor (LXRα/FXR or PPARα)-mediated lipid homeostasis.
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