Abstract 263: Adipose Differentiation Related Protein: A Possible Target for the Prevention and Treatment of Atherosclerosis
Background. Adipose Differentiation Related Protein (ADFP) is a member of PAT-domain lipid droplet (LD) family of proteins that is induced during lipid accumulation in different cell types and, in addition, ADFP overexpression has been reported to inhibit lipid efflux and stimulate lipid accumulation and LD formation in cultured macrophages. We previously reported that genetic inactivation of ADFP protects against diet-induced fatty liver in mice. Because cholesterol ester deposition in LD-laden foam cells is a key feature in atherogenesis, we examined whether ADFP deficiency modulates atherosclerosis development in apoE-deficient mice.
Results. The absence of ADFP had no effect on body weight, plasma lipids and lipoprotein profiles in apoE−/ − mice fed regular chow, but reduced atherosclerosis development by ~50% in both male and female mice. Electron microscopy analysis of foam cells of ADFP−/ − apoE−/ − mice showed a greatly reduced number of cytoplasmic LDs. In contrast, the rate of aortic atherosclerosis development in ADFP−/ − /apoE−/ − mice was not different from ADFP+/+/apoE−/ − mice when they were fed a high-fat diet (HFD); foam cells from these groups of animals also showed similar amounts of LDs, indicating that in the presence of a high lipid input mice without ADFP preserve their ability to store the additional intracellular cholesterol in LDs. Analysis of peritoneal macrophages showed that the absence of ADFP does not affect lipoprotein binding and uptake, but lowers the rate of cholesterol esterification and increases that of cholesterol efflux in the absence of significant changes in the level of different molecules involved in intracellular cholesterol homeostasis, including SR-A, CD36, ACAT1, ABCA1, ABCG1, SR-BI, etc. The absence of ADFP was not associated with compensatory changes in the expression of other PAT-domain LD proteins, TIP47, S3–12, or perilipin; it also had no demonstrable effect on cell viability or function.
Conclusions. ADFP regulates cholesterol storage and LD and foam-cell formation in macrophages and is a major determinant of atherogenesis. It may be a novel target for the prevention or treatment of atherosclerosis.