Lysosomal acid lipase and atherosclerosis.
OBJECTIVE
Atherosclerosis remains the leading cause of death in the developed countries. In addition to lipid-lowering drugs - statins, dietary control, and exercise, new approaches are needed for the treatment and prevention of atherosclerosis. This review will focus on the role(s) of lysosomal acid lipase and its use as an enzyme therapy to reduce atherosclerotic lesions in a mouse model and to examine the molecular basis supporting this novel strategy and its mechanism of effect.


RESULTS
Administration of human lysosomal acid lipase via tail vein into mice with atherosclerosis eliminates early aortic and coronary ostial lesions and reduces lesional size in advanced disease. The reduction of advanced lesional area is related to decreases in foamy macrophages, collagen positive areas, and necrotic areas. Compared with sham-treated mice, the human lysosomal acid lipase-treated mice also have reduced levels of plasma cholesteryl esters, and reduced levels of hepatic cholesterol and triglycerides.


CONCLUSIONS
These studies indicate that administrated lysosomal acid lipase affects the atherogenesis by at least two mechanisms: (1) direct targeting of lesional macrophages with resultant decreases in cholesteryl esters and triglyceride in the lysosomes of macrophages in the lesions; (2) systemic effects that mediate the liver to reduce the hepatic cholesteryl ester and triglyceride release, possibly leading to reduced production of VLDL and LDL.
Du
Hong
H
The Children's Hospital Research Foundation of Cincinnati Children's Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229-3039, USA.
Grabowski
Gregory A
GA
D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology*; D002788:Cholesterol Esters; D002986:Clinical Trials as Topic; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000502:physiology*; D008247:Lysosomes / Q000201:enzymology* / Q000378:metabolism; D008264:Macrophages; D008954:Models, Biological; D014280:Triglycerides / Q000378:metabolism
D002788:Cholesterol Esters; D018076:DNA, Complementary; D014280:Triglycerides; D008049:Lipase