Lipoprotein lipase mediates an increase in the selective uptake of high density lipoprotein-associated cholesteryl esters by hepatic cells in culture

The effects of diabetes and lipoprotein lipase (LpL) on plasma lipids were studied in mice expressing human apolipoprotein B (HuBTg). Our overall objective was to produce a diabetic mouse model in which the sole effects of blood glucose elevation on atherosclerosis could be assessed. Mice were made diabetic by intraperitoneal injection of streptozotocin, which led to a 2-to 2.5-fold increase in plasma glucose. Lipids were assessed in mice on chow and on an atherogenic Western type diet (WTD), consisting of 21% (wt/wt) fat and 0.15% (wt/wt) cholesterol. Plasma triglyceride and cholesterol were the same in diabetic and nondiabetic mice on the chow diet. On the WTD, male diabetic HuBTg mice had a Ͼ 50% increase in plasma cholesterol and more very low density lipoprotein (VLDL) cholesterol and triglyceride as assessed by FPLC analysis. A Triton study showed no increase in triglyceride or apolipoprotein B production, suggesting that the accumulation of VLDL was due to a decrease in lipoprotein clearance. Surprisingly, the VLDL increase in these mice was not due to a decrease in LpL activity in postheparin plasma. To test whether LpL overexpression would alter these diabetes-induced lipoprotein changes, HuBTg mice were crossed with mice expressing human LpL in muscle. LpL overexpression reduced plasma triglyceride, but not cholesterol, in male mice on WTD. Aortic root atherosclerosis assessed in 32-week-old mice on the WTD was not greater in diabetic mice. In summary, diabetes primarily increased plasma VLDL in HuBTg mice. LpL activity was not decreased in these animals. However, additional LpL expression eliminated the diabetic lipoprotein changes. These mice did not have more atherosclerosis with diabetes.

Section: Discussionmentioning

confidence: 99%

Streptozotocin-induced diabetes in human apolipoprotein B transgenic mice: effects on lipoproteins and atherosclerosis

Kako

Huang

Yang

et al. 1999

“…Thus, selective cholesteryl ester (CE) uptake may be even more important in mice and other CETP-deficient animals. Recently, LPL has been shown to aid in the selective uptake of HDL-CE by macrophages and hepatic cells (57,58). Thus, in the absence of CETP and apoE, which may also aid in the bridging of lipoproteins to the cell surface (59), a reduction in the amount of LPL protein may compromise the ability of HDL to deliver its CEs to the liver.…”

Section: Discussionmentioning

confidence: 99%

Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis

Clee

Bissada

Miao

et al. 2000

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro-or anti-atherogenic effects, depending on its localization. Decreased plasma LPL activity is associated with the high triglyceride (TG)-low HDL phenotype that is often observed in patients with premature vascular disease. In contrast, in the vessel wall, decreased LPL may be associated with less lipoprotein retention due to many potential mechanisms and, therefore, decreased foam cell formation. To directly assess this hypothesis, we have distinguished between the effects of variations in plasma and/or vessel wall LPL on atherosclerosis susceptibility in apoE-deficient mice. Reduced LPL in both plasma and vessel wall (LPL ؉ / ؊ E ؊ / ؊ ) was associated with increased TG and increased total cholesterol (TC) compared with LPL ؉ / ؉ E ؊ / ؊ sibs. However despite their dyslipidemia, LPL ؉ / ؊ E ؊ / ؊ mice had significantly reduced lesion areas compared to the LPL ؉ / ؉ E ؊ / ؊ mice. Thus, decreased vessel wall LPL was associated with decreased lesion formation even in the presence of reduced plasma LPL activity. In contrast, transgenic mice with increased plasma LPL but with no increase in LPL expression in macrophages, and thus the vessel wall, had decreased TG and TC and significantly decreased lesion areas compared with LPL ؉ / ؉ E ؊ / ؊ mice. This demonstrates that increased plasma LPL activity alone, in the absence of an increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis.Taken together, these results provide in vivo evidence that the contribution of LPL to atherogenesis is significantly influenced by the balance between vessel wall protein (pro-atherogenic) and plasma activity (anti-atherogenic). -Clee, S.

“…Finally, our report describes a novel non-lipolytic function for lipoprotein-bound LPL that comes in addition to other functions recently described. Several works have indeed demonstrated that LPL may facilitate the interaction of different lipoproteins with various tissues by mechanisms involving heparan sulfate proteoglycans and/or membrane receptors (35)(36)(37)(38)(39)(40)(41)(42). Thus LPL appears now clearly as a protein that exerts multiple functions in lipoprotein metabolism, functions that do not necessarily result from its lipolytic activity.…”

Section: Discussionmentioning

confidence: 99%

VLDL-bound lipoprotein lipase facilitates the cholesteryl ester transfer protein-mediated transfer of cholesteryl esters from HDL to VLDL

Pruneta

Pulcini²,

Lalanne³

et al. 1999

In recent years, it has been established that lipoprotein lipase (LPL) is partly associated with circulating lipoproteins. This report describes the effects of physiological amounts of very low density lipoprotein (VLDL)-bound LPL on the cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester transfer (CET) from high density lipoprotein (HDL) to VLDL. Three patients with severe LPL deficiency exhibited a strong decrease in net mass CET that was more than 80% lower than that of common hypertriglyceridemic subjects. Recombination experiments showed that this was due to an abnormal behavior of the VLDL fraction. Replacement of the latter by normal VLDL totally normalized net mass CET. We therefore prepared VLDL containing controlled amounts of bound LPL that we used as CE acceptors in experiments involving unidirectional radioisotopic CET measurements. These were carried out either in the absence or in the presence of inhibitors of LPL lipolytic activity. When LPL-induced lipolysis was totally blocked, the stimulating effect of the enzyme on the CETP-dependent CET was only reduced by about 50%, showing that it did not entirely result from its lipolytic action. These data were dependent upon neither the type of LPL inhibitor (E600 or THL) nor the source of CETP (delipidated plasma or partially purified CETP). Thus, in addition to the well-known stimulating effect of LPL-dependent lipolysis on CET, our work demonstrates that physiological amounts of VLDLbound LPL may facilitate CET through a mechanism partially independent of its lipolytic activity. -Pruneta, V., T. Pulcini, F. Lalanne, C. Marçais, F. Berthezène, G. Ponsin, and P. Moulin. VLDL-bound lipoprotein lipase facilitates the cholesteryl ester transfer protein-mediated transfer of cholesteryl esters from HDL to VLDL.