Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice.
Hepatic lipase (HL) has a well-established role in lipoprotein metabolism. However, its role in atherosclerosis is poorly understood. Here we demonstrate that HL deficiency raises the proatherogenic apoB-containing lipoprotein levels in plasma but reduces atherosclerosis in lecithin cholesterol acyltransferase (LCAT) transgenic (Tg) mice, similar to results previously observed with HL-deficient apoE-KO mice. These findings suggest that HL has functions that modify atherogenic risk that are separate from its role in lipoprotein metabolism. We used bone marrow transplantation (BMT) to generate apoE-KO and apoE-KO x HL-KO mice, as well as LCAT-Tg and LCAT-Tg x HL-KO mice, chimeric for macrophage HL gene expression. Using in situ RNA hybridization, we demonstrated localized production of HL by donor macrophages in the artery wall. We found that expression of HL by macrophages enhances early aortic lesion formation in both apoE-KO and LCAT-Tg mice, without changing the plasma lipid profile, lipoprotein lipid composition, or HL and lipoprotein lipase activities. HL does, however, enhance oxidized LDL uptake by peritoneal macrophages. These combined data demonstrate that macrophage-derived HL significantly contributes to early aortic lesion formation in two independent mouse models and identify a novel mechanism, separable from the role of HL in plasma lipoprotein metabolism, by which HL modulates atherogenic risk in vivo.
Nong
Zengxuan
Z
Molecular Disease Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
Gonzalez-Navarro
Herminia
H
Amar
Marcelo
M
Freeman
Lita
L
Knapper
Catherine
C
Neufeld
Edward B
EB
Paigen
Beverly J
BJ
Hoyt
Robert F
RF
Fruchart-Najib
Jamila
J
Santamarina-Fojo
Silvia
S
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D016026:Bone Marrow Transplantation; D005260:Female; D015870:Gene Expression; D008049:Lipase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
D001057:Apolipoproteins E; D008055:Lipids; D012333:RNA, Messenger; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008049:Lipase; D008071:Lipoprotein Lipase