Date of Award

2013

Degree Type

Thesis

Department

Biological, Geological and Environmental Sciences

First Advisor

Sehayek, Ephraim

Subject Headings

Cholesterol -- Metabolism, Carrier proteins, Reverse cholesterol transport Ezetimibe Abcg5 and Abcg8

Abstract

Reverse cholesterol transport (RCT) consists of the transfer of cholesterol from peripheral tissues for excretion in the feces. The RCT from macrophages in atherosclerotic lesions is an important determinant of arterial wall atherosclerotic lesion formation. Previous studies by our group have shown that treatment with ezetimibe (EZ), a potent inhibitor of cholesterol absorption from the intestine, results in a 2-6 fold increase in RCT. To determine whether EZ may increase RCT by mechanisms that are independent of its well established cholesterol absorption inhibitory effects, we examined the expression of genes involved in the RCT pathway in the jejunum and liver tissues of C57BL/6J mice fed a chow diet or chow supplemented with 0.005 EZ. These studies revealed that treatment with EZ specifically stimulates the expression of Abcg5/Abcg8 in the liver, but not in the intestine. Further experiments clearly demonstrated that stimulation of liver Abcg5/Abcg8 expression was due to the inhibition of cholesterol absorption from the intestine and not a direct effect of EZ in the liver. This conclusion was further supported by the absence of an ABCG5/ABCG8 expression response to treatment of primary human hepatocytes with a glucuronated form of EZ. Finally, we found that the induction of liver Abcg5/Abcg8 accounts for nearly 50 of the EZ-dependent stimulation of RCT. To our knowledge, our studies are the first to demonstrate increased liver Abcg5/Abcg8 expression in response to EZ treatment which, in conjunction with suppression of intestinal cholesterol absorption, synergistically stimulate the macrophage-to-feces RCT

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