Role of macrophage-derived lipoprotein lipase in lipoprotein metabolism and atherosclerosis.
Lipoprotein lipase (LPL) synthesis by macrophages is upregulated in early atherogenesis, implicating the possible involvement of LPL in plaque formation. However, it is still unclear whether macrophage-derived LPL displays a proatherosclerotic or an antiatherosclerotic role in atherosclerotic lesion development. In this study, the role of macrophage-derived LPL on lipid metabolism and atherosclerosis was assessed in vivo by transplantation of LPL-deficient (LPL-/-) and wild-type (LPL+/+) bone marrow into C57BL/6 mice. Eight weeks after bone marrow transplantation (BMT), serum cholesterol levels in LPL-/--->C57BL/6 mice were reduced by 8% compared with those in LPL+/+-->C57BL/6 mice (P:<0.05, n=16), whereas triglycerides were increased by 33% (P:<0.05, n=16). Feeding the mice a high-cholesterol diet increased serum cholesterol levels in LPL-/--->C57BL/6 and LPL+/+-->C57BL/6 mice 5-fold and 9-fold, respectively, resulting in a difference of approximately 50% (P:<0. 01) after 3 months on the diet. No effects on triglyceride levels were observed under these conditions. Furthermore, serum apolipoprotein E levels were reduced by 50% in the LPL-/--->C57BL/6 mice compared with controls under both dietary conditions. After 3 months on a high-cholesterol diet, the atherosclerotic lesion area in LPL-/--->C57BL/6 mice was reduced by 52% compared with controls. It can be concluded that macrophage-derived LPL plays a significant role in the regulation of serum cholesterol, apolipoprotein E, and atherogenesis, suggesting that specific blockade of macrophage LPL production may be beneficial for decreasing atherosclerotic lesion development.
Van Eck
M
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, Leiden, The Netherlands. M.Eck@LACDR.LeidenUniv.nl
Zimmermann
R
R
Groot
P H
PH
Zechner
R
R
Van Berkel
T J
TJ
D000818:Animals; D001057:Apolipoproteins E / Q000097:blood; D001161:Arteriosclerosis / Q000097:blood / Q000201:enzymology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary; D005260:Female; D006801:Humans; D007455:Iodine / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008111:Liver Function Tests; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D007455:Iodine; D002784:Cholesterol; D008071:Lipoprotein Lipase