Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo

Abstract

Expression of lipoprotein lipase (LPL) by the macrophage has been proposed to promote foam cell formation and atherosclerosis, primarily on the basis of in vitro studies. LPL-deficient mice might provide a model for testing the role of LPL secretion by the macrophage in an in vivo system. Unfortunately, homozygous deficiency of LPL in the mouse is lethal shortly after birth. Because the fetal liver is the major site of hematopoiesis in the developing fetus, transplantation of C57BL/6 mice with LPL -/-fetal liver cells (FLCs) was used to investigate the physiologic role of macrophage LPL expression in vivo. Thirty-four female C57BL/6 mice were lethally irradiated and reconstituted with FLCs from day 14 LPL +/+ , LPL +/-, and LPL -/-donors. No significant differences were detected in plasma levels of post-heparin LPL activity or in serum cholesterol or triglyceride levels between the 3 groups on either a chow diet or an atherogenic diet. After 19 weeks on the atherogenic diet, aortae were collected for quantitative analysis of the extent of aortic atherosclerosis. LPL expression was detected by immunocytochemistry and in situ hybridization in macrophages of aortic atherosclerotic lesions of LPL +/+ →C57BL/6 and LPL +/-→C57BL/6 mice, but not in LPL -/-→C57BL/6 mice, whereas myocardial cells expressed LPL in all groups. The mean aortic lesion area was reduced by 55% in LPL -/-→C57BL/6 mice compared with LPL +/+ →C57BL/6 mice and by 45% compared with LPL +/-→C57BL/6 mice, respectively. These data demonstrate in vivo that LPL expression by macrophages in the artery wall promotes foam cell formation and atherosclerosis.

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

“…Transplantation of fetal liver cells or bone marrow of LPL-deficient mice into C57BL/6 mice or LDL receptor-KO mice reduces atherosclerosis, suggesting that LPL in the arterial wall is atherogenic. 13,14,39 We also considered the possible direct impact of LPL secreted by arterial wall on the increased extent of atherosclerosis as the LPL transgene was also expressed in macrophage and aorta as detected by Northern blot analysis (data not shown). Immunohistochemical staining results showed that in transgenic rabbits, a small amount of LPL proteins was located extracellularly in the lesions.…”

“…Until now, most studies have focused on whether LPL affects cholesterol-rich remnant clearance in an antiatherogenic manner 6 or whether macrophage-derived LPL in the arterial wall is proatherogenic. 13,14 The antiatherogenic roles of LPL are mainly mediated by the enhanced hepatic clearance of remnant lipoproteins, 15 which leads to lowering plasma cholesterol, 16 whereas the proatherogenic functions of LPL are mainly attributed to the noncatalytic function of vascular cellderived LPL, which may not only promote the retention of atherogenic lipoproteins in the intima 17,18 but also aid in the uptake of lipoproteins by macrophages as well. 19 Moreover, the process of the hydrolysis of TG-rich lipoproteins by LPL also leads to the generation of IDLs and the enhancement of the conversion of large LDLs to small and dense LDLs.…”

The role of lipoprotein lipase in adipose tissue development and metabolism

“…19 Importantly, bone marrow transplantation experiments revealed that the absence of LPL in monocytesamacrophages markedly reduces the susceptibility of C57B16 mice to develop atherosclerotic lesions when fed a high cholesterol diet. 20,21 In contrast to the bene®cial role of high LPL activities in peripheral tissues to ensure low TG and high HDL cholsterol levels, thereby decreasing the atherosclerotic risk, high LPL activities in macrophages of mice appear to induce lipid accumulation, foam cell formation and atherosclerosis susceptibility.…”

Proliferative Effect of Lipoprotein Lipase on Human Vascular Smooth Muscle Cells

“…20,21 Furthermore, recent studies indicate that LPL enhances cellular proteoglycan production 22 and promotes foam cell formation and atherosclerosis in vivo. 23 VSMC migration and proliferation are typical features of intimal hyperplasia and atherogenesis. 24 These biological processes are mediated by cytokines and growth factors released by infiltrating inflammatory cells and neighboring endothelial cells.…”