Abstract 104: Apolipoprotein D: Implications for Multiple Roles in Lipid Metabolism

Abstract

Introduction- ApoD is a ubiquitously expressed protein that binds small hydrophobic ligands and is a minor component of lipoproteins. Polymorphisms of the human ApoD gene are associated with lipid abnormalities, specifically the reduction of HDL and ApoA1 levels. In fact, hepatic overexpression of ApoD has been shown to regulate the amount of plasma triglycerides. ApoD is also upregulated in human and mouse models of atherosclerosis, and is localized in cell types involved in atherosclerotic lesion formation. These data suggest that ApoD plays a role in lipid metabolism by modulating cellular processes in vascular cells during atherogenesis. In this study, our objective is to identify the role(s) of ApoD in lipid metabolism and to elucidate the mechanisms involved in this process. Methods and Results- To accomplish our objective, we used a two-pronged approach. We first studied the effect of ApoD on lipid metabolism on a chow diet. There was no significant difference between the levels of plasma cholesterol in ApoD -/- and wild-type mice on a chow diet; however, hepatic cholesterol levels had more than doubled. A 96-gene PCR array was used to assess differential expression of genes involved in fatty liver biogenesis. There was at least a 2-fold difference in expression in about 10 genes involved in insulin/glucose signaling, lipogenesis, and inflammation in the ApoD -/- mice. We then studied the effect of a Western diet in the ApoD -/- mice, which showed a significant reduction in plasma LDL-cholesterol and HDL-cholesterol when compared to wild-type mice. Analysis of the HDL fractions after subjecting plasma to a Fast Protein Liquid Chromatography column revealed increased levels of ApoA1 and Lecithin Cholesterol Acyl Transferase (LCAT) activity in ApoD -/- mice. Conclusion- A decrease in plasma cholesterol and an increase in ApoA1 and LCAT activity suggest that ApoD may play a role in the catabolism of HDL particles, resulting in lower plasma cholesterol levels in ApoD -/- mice. Our current data implies that ApoD plays a multifunctional role in lipid metabolism and the mechanism by which this occurs must be further examined.