Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice.
Plasma sphingomyelin (SM) has been suggested as a risk factor for coronary heart disease independent of cholesterol levels. A decrease of SM in lipoproteins is known to improve the activities of lecithin:cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) in vitro. Inhibition of SM biosynthesis may reduce lipoprotein SM content and thus improve cholesterol distribution in lipoproteins by enhancing reverse cholesterol transport and clearance of triglyceride-rich lipoproteins. To examine this hypothesis, ApoE KO mice were fed a western diet and treated for 4 weeks with various concentrations of myriocin, a specific inhibitor of serine palmitoyltransferase. Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner. In addition, myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol. Observed lipid-lowering effects of myriocin were associated with suppression of HMG CoA reductase and fatty acid synthase via reduced levels of SREBP-1 RNA and protein. Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL. Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice. In conclusion, inhibition of sphingolipid biosynthesis can be a novel therapeutic target for dyslipidemia and atherosclerosis.
Park
Tae-Sik
TS
Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. tp2156@columbia.edu
Panek
Robert L
RL
Rekhter
Mark D
MD
Mueller
Sandra Bak
SB
Rosebury
Wendy S
WS
Robertson
Andrew
A
Hanselman
Jeffrey C
JC
Kindt
Erick
E
Homan
Reynold
R
Karathanasis
Sotirios K
SK
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism*; D015153:Blotting, Western; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D013109:Sphingomyelins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D005229:Fatty Acids, Monounsaturated; D007166:Immunosuppressive Agents; D013109:Sphingomyelins; D051780:Sterol Regulatory Element Binding Protein 1; D012313:RNA; C001996:thermozymocidin