Masters Thesis

Apomine, an Inhibitor of Cholesterol Synthesis, Increases Secretion of Apolipoprotein E from Human Astrocytoma and Liver Hepatocyte Cells

Apolipoprotein E (apoE) is a crucial protein involved with cholesterol homeostasis and is a genetic risk factor for Alzheimer’s disease. Apomine and simvastatin are potent cholesterol-reducing compounds that mediates their actions through inhibition of HMGCoA-reductase, the rate-limiting enzyme in cholesterol synthesis. We hypothesize that these two compounds increase apoE secretion from human HepG2 liver hepatocyte cells to capture cholesterol from extracellular sources to compensate for their sterol-deprived state. Treatment of HepG2 liver hepatocyte cells with apomine in serum-free medium leads to a significant increase in secreted apoE that is suppressed in the presence of LDL cholesterol added to the culture medium. Consistent with our hypothesis, we found that Apomine and simvastatin increase expression of apoE along with the lipid membrane receptors: LDLR and ApoER2. These results indicate that the presence of cholesterol in the growth medium suppresses the cell’s drive to search for cholesterol through increased apoE secretion. Moreover, the results suggest that increase in apoE expression by apomine and simvastatin is dependent upon SREBP2, responsible for cellular cholesterol regulation. This novel regulation of apoE expression by apomine is relevant to the fields of Alzheimer’s disease and other cholesterol homeostasis related processes.

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