Relative roles of the LDL receptor, the LDL receptor-like protein, and hepatic lipase in chylomicron remnant removal by the liver.

562

118

The plasma clearance of intestinally derived remnant lipoproteins by the liver is a process that likely involves three steps. Our model suggests that the initial rapid clearance by the liver begins with sequestration of the remnants within the space of Disse, where apolipoprotein E secreted by hepatocytes enhances remnant binding and uptake. Heparan sulfate proteoglycans (HSPG), which are also abundant in the space of Disse, mediate this enhanced binding. Next, the remnants undergo further processing in the space of Disse by hepatic and lipoprotein lipases, which may also serve as ligands mediating remnant uptake. The final step, endocytosis by hepatocytes, appears to be mediated, at least in part, by the low density lipoprotein (LDL) receptor and by the LDL receptor-related protein (LRP). Cell-surface HSPG play a critical role in remnant uptake, not only in the important initial sequestration or capture step in the space of Disse, but also as an essential or integral component of the HSPG-LRP pathway. In addition, HSPG appear to function alone as a receptor and display unique handling properties for specific isoforms of apolipoprotein E.-Mahley, R. W., and Z-S. Ji. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E.

Section: Role Of Hl In Remnant Metabolismmentioning

confidence: 99%

Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E

Mahley

Zhong

1999

562

118

“…Chylomicron remnants are formed after the hydrolysis of triglycerides, from intestine-derived chylomicrons, by lipoprotein lipase (LPL) and are rapidly removed from the circulation. The principal tissue site of removal is the liver (1,2). The mechanisms responsible for this rapid clearance are becoming more defined.…”

mentioning

confidence: 99%

“…1 Present address: First Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya 663, Japan. 2 To whom correspondence should be addressed.…”

mentioning

confidence: 99%

Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages

Fujioka

Cooper

Fong

1998

The processes responsible for the uptake of chylomicron remnants by macrophages were investigated using freshly isolated cells from low density lipoprotein (LDL) receptor, very low density lipoprotein (VLDL) receptor and apolipoprotein E knockout mice. In peritoneal macrophages from normal mice, the metabolism of chylomicron remnants was inhibited 40% by anti-LDL receptor antibody and 60% by a high concentration of receptor-associated protein (RAP). Together they reduced the amount processed by 70%. Digestion of cell proteoglycans decreased remnant degradation by 20% while the addition of acetyl-LDL had no effect. When LDL receptors were absent, the absolute rates of metabolism were less than that of normal cells and were not inhibited by the anti-LDL receptor antibody; the rates, however, were reduced to less than half by RAP. These suggest that the LDL receptor-related protein (LRP) or another LDL receptor family member(s) contributes to chylomicron remnant uptake and becomes the major mechanism of uptake when LDL receptors are absent. In contrast, the VLDL receptor was not involved as its absence did not affect chylomicron remnant metabolism. Similarly, the absence of apoE production did not affect the amount of remnant uptake; however, the proportion that was sensitive to RAP was eliminated. The level of LRP expression was not altered in these cells whereas there was a decrease in LDL receptors. This suggests that the apoE content of chylomicron remnants is sufficient for its recognition by LDL receptors but additional apoE is required for its uptake by the LRP and that there is an up-regulation of a non-LDL receptor family mechanism in apoE deficiency. Together these studies suggest that even in the absence of LDL receptors or apoE secretion, chylomicron remnants could contribute to lipid accumulation in the artery wall during atherogenesis.-Fujioka, Y., A. D. Cooper, and L. G. Fong. Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages.

“…These studies were done in cell culture and their relevance to in vivo behavior remains to be established. In vivo anti-hepatic lipase antibody infusion results in accumulation of remnant-like particles (29) and delayed removal of chylomicron remnants in rats (3) and mice (4). While these observations are consistent with a role for hepatic lipase in lipoprotein transport in vivo, they are not proof that one exists.…”

Section: Discussionmentioning

confidence: 97%

“…On the other hand, the localization of the enzyme to tissues that have major roles in sterol metabolism suggests it might have a role in delivering lipids, particularly cholesterol, to these tissues. Consistent with this postulate, studies with antibodies in vivo (3,4) have suggested that the enzyme may play a role in the hepatic removal of chylomicron remnants, particles that transport dietary cholesterol and sterol vitamins to the liver. Previous cell culture experiments by Aviram, Bierman, and Chait (5) suggested that the enzyme could accelerate the removal of LDL by cells in culture.…”

mentioning

confidence: 78%

Accelerated lipoprotein uptake by transplantable hepatomas that express hepatic lipase

Donner

Choi

Komaromy

et al. 1998

To test the hypothesis that hepatic lipase plays a key role in lipoprotein removal in vivo, a novel system was used. Hepatoma cells (HTC 7288c) were transfected with a cDNA encoding hepatic lipase in culture and grown as solid tumors in vivo. In culture, transfected cells degraded chylomicron remnants and low density lipoprotein (LDL) somewhat more efficiently than untransfected cells. Tumors from the transplanted cells produced hepatic lipase localized to the surface of tumors from transfected cells but not tumors from non-transfected cells, grown in the same rat. The tumors from transfected cells removed, per gm of tissue, 34% ( P Ͻ 0.001) more 125 I-labeled LDL than tumors from non-transfected cells in the same animal. The uptake of chylomicron remnants (by tumors from transfected cells) was also modestly enhanced (15 ؎ 6%, P Ͻ 0.005). There were no differences in the uptake of 125 I-labeled albumin or 125 I-labeled asialoglycoprotein. Compared to the liver, the untransfected tumors took up 12%, and the transfected tumors took up about 18% as much LDL per gram of tissue. The uptake of chylomicron remnants compared to liver was far lower. Both types of tumors had about twice as much LDL receptor related protein as the liver. Wild-type tumors had the highest level of LDL receptor, twice hepatic lipasesecreting tumors, and six times that of the liver. Using the novel approach of transfecting transplantable tumor cells with hepatic lipase, the ability of hepatic lipase to facilitate the removal of apoB-containing lipoproteins was demonstrated. The liver still removes low density lipoprotein and especially chylomicron remnants more rapidly than the tumors, suggesting factors in addition to hepatic lipase and LDL receptor level play a major role in hepatic lipoprotein removal.-Donner, C., S. Choi, M. Komaromy, and A. D. Cooper. Accelerated lipoprotein uptake by transplantable hepatomas that express hepatic lipase.