Inhibition of glycosphingolipid synthesis induces a profound reduction of plasma cholesterol and inhibits atherosclerosis development in APOE*3 Leiden and low-density lipoprotein receptor-/- mice.
OBJECTIVE
The iminosugar N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase catalyzing glycosphingolipid (GSL) biosynthesis, ameliorates diabetes and reduces liver steatosis in ob/ob mice. Because an accumulation of sphingolipids, including sphingomyelin and GSLs, has been reported in atherosclerotic lesions in animal models and in humans, the objective of this study was to determine whether AMP-DNM also exerts beneficial effects on the development of atherosclerosis.


RESULTS
APOE*3 Leiden mice, maintained on a high-cholesterol diet, were treated for up to 18 weeks with AMP-DNM. The iminosugar prevented hyperlipidemia, generated a less atherogenic lipid profile, and induced a dramatic reduction in the development of atherosclerotic lesions. At the highest dose, no lesions were detectable. The effect of AMP-DNM was associated with a decrease in liver cholesterol, an increase in bile secretion, and enhanced excretion of cholesterol in the feces. Similar effects of AMP-DNM were observed in mice deficient for the low-density lipoprotein receptor.


CONCLUSIONS
By lowering plasma cholesterol, the iminosugar AMP-DNM dramatically reduces the development of atherosclerosis in APOE*3 Leiden and low-density lipoprotein receptor -/- mice. Thus, targeting GSL synthesis may be a new treatment modality to prevent cardiovascular disease.
Bietrix
Florence
F
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, the Netherlands.
Lombardo
Elisa
E
van Roomen
Cindy P A A
CP
Ottenhoff
Roelof
R
Vos
Mariska
M
Rensen
Patrick C N
PC
Verhoeven
Arthur J
AJ
Aerts
Johannes M
JM
Groen
Albert K
AK
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005243:Feces / Q000737:chemistry; D005260:Female; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006028:Glycosphingolipids / Q000096:biosynthesis*; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; C496281:N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin; D011973:Receptors, LDL; D017485:1-Deoxynojirimycin; D002784:Cholesterol; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D000218:Adamantane