Peptides derived from serum amyloid A prevent, and reverse, aortic lipid lesions in apoE-/- mice.

Macrophages (M � ) at sites of acute tissue injury accumulate and export cholesterol quickly. This metabolic activity is likely dependent on the physiological function of a major acute-phase protein, serum amyloid A 2.1 (SAA2.1), that is synthesized by hepatocytes as part of a systemic response to acute injury. Our previous studies using choles- terol-laden J774 mouse Mshowed that an N-terminal do- main of SAA2.1 inhibits acyl-CoA:cholesterol acyltransferase activity, and a C-terminal domain enhances cholesteryl ester hydrolase activity. The net effect of this enzymatic regula- tion is to drive intracellular cholesterol to its unesterified state, the form readily exportable to an extracellular accep- tor such as HDL. Here, we demonstrate that these domains from mouse SAA2.1, when delivered in liposomal formula- tion, are effective at preventing and reversing aortic lipid lesions in apolipoprotein E-deficient mice maintained on high-fat diets. Furthermore, mouse SAA peptides, in liposo- mal formulation, are effective at regulating cholesterol ef- flux in THP-1 human M � , and homologous domains from human SAA are effective in mouse J774 cells. These pep- tides operate at the level of the foam cell in the reverse cho- lesterol pathway and therefore may be used in conjunction with other agents that act more distally in this process. Such human peptides, or small molecule mimics of their structure, may prove to be potent antiatherogenic agents in humans. —Tam, S. P., J. B. Ancsin, R. Tan, and R. Kisilevsky. Peptides derived from serum amyloid A prevent, and re- verse, aortic lipid lesions in apoE � / � mice. J. Lipid Res. 2005. 46: 2091-2101.