The Ah receptor (AHR) has traditionally been studied in terms of its ability to mediate transcriptional effects through binding to dioxin-response elements (DRE). We have developed a transgenic mouse model, which expresses a mutant AHR-A78D that fails to bind to dioxin-response element, to test whether the AHR suppresses gene expression in the liver. Many of the genes repressed upon activation of the AHR with the agonist beta-naphthoflavone are genes directly involved in the synthesis and homeostatic control of cholesterol. Additionally, recently published studies have shown that BNF represses expression of genes involved in cholesterol homeostasis and can repress the secretion of cholesterol in primary human hepatocytes. Recently, we have established that SGA360 is a selective Ah receptor ligand that can repress acute-phase gene expression through the AHR without inducing DRE-mediated activity. Furthermore, preliminary results in this application suggest that SGA360 can also repress cholesterol synthesis. These results have led to the central hypothesis that selective Ah receptor modulators (SAhRM) exhibit an ability to repress expression of genes that mediate cholesterol synthesis and thus have therapeutic potential for treating a number of disease states. The first specific aim will examine the ability of SAhRM to modulate cholesterol synthesis in primary human hepatocytes and mice in the presence and absence of statins.
The second aim will test the ability of SGA360 to attenuate plaque formation in the atherosclerosis model, Apo E-/- mice.
The third aim will determine the mechanism(s) of SAhRM-induced transcriptional repression of genes involved in cholesterol synthesis.
The fourth aim will use targeted metabolite profiling to determine the full impact of SAhRM treatment on overall lipid metabolism in primary human hepatocytes. In particular, key metabolites in the cholesterol synthesis pathway will be examined. This is particularly important to examine whether SAhRM can be used therapeutically. The attenuation of cholesterol synthesis through the use of SAhRM has the potential to impact a variety of diseases, such as atherosclerosis and nonalcoholic fatty liver disease.
Activation of the Ah receptor (AHR) has been demonstrated to repress the expression of a wide array of genes involved in cholesterol homeostasis in liver. Selective AHR ligands can mediate cholesterol biosynthetic gene repression without eliciting a dioxin response element-driven transcriptional response. These studies will explore the mechanism of selective AHR ligand activity in the absence and presence of a statin, which may lead to the development of the AHR as a therapeutic target to treat diseases such as nonalcoholic fatty liver disease or arthrosclerosis.
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