Receptor-mediated catabolism of homologous low density lipoproteins in cultured pig hepatocytes.

Pangburn, Sharon; Newton, Roger S.; Chang, Chien‐Wen; Weinstein, David; Steinberg, Daniel

doi:10.1016/s0021-9258(19)69612-2

Cited by 88 publications

(5 citation statements)

References 48 publications

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“…The Ca2+ dependence of 125I-LDL uptake and degradation could not be examined satisfactorily because the cells detached from the culture plates in Ca2+-free medium or in the presence of EDTA. These characteristics of 125I-LDL degradation were similar to those recently reported by Pangburn et al (1981). The relation between degradation and uptake was not reported for most of their experiments, but their findings also suggested the existence in hepatocytes of a receptor similar to the peripheral LDL receptor.…”

Section: Discussionsupporting

confidence: 87%

“…In a separate experiment with 125I-LDL, the proportion of Cl3CCOOH-soluble radioactivity in the peroxidation-resistant fraction increased from 11.7% to 57.2%, or 5-fold, in the presence of 3 X 10-5 M 3-iodotyrosine. The findings in both experiments suggested strongly that free iodide was produced primarily from the proteolytic products rather than directly from the labeled lipoproteins and supported the validity of the practice by which lipoprotein degradation in liver has been determined from the total Cl3CCOOH-soluble radioactivity produced (Pangburn et al, 1981;. On the basis of the production of total Cl3CCOOFIsoluble radioactivity, hepatocytes degraded 125I-HDL at the rate of 27 ± 5 ng h-1 (mg of cell protein)-1 (mean ± SE, n = 7) and 125I-LDL at the rate of 103 ± 37 ng h-1 (mg of cell protein)-1 (mean ± SE, = 4) when assayed at substrate concentrations of 5 ug/mL 125I-labeled lipoprotein-protein.…”

Section: Resultssupporting

confidence: 56%

“…Evidence for high-affinity HDL or LDL uptake has been presented by others in freshly suspended rat liver parenchymal and nonparenchymal cells (Van Berkel et al, 1980;Ose et al, 1980;Ose et al, 1979; and in cultured rabbit and pig hepatocytes (Soltys & Portman, 1979;Pangburn et al, 1981), and a binding site with properties of the peripheral LDL receptor has been detected in liver microsomes from several species (Kovanen et al, 1979(Kovanen et al, , 1981Kita et al, 1981;Hui et al, 1981). There is some suggestion in several of these studies of the presence of a site(s) similar to the lipoprotein binding site as well.…”

Section: Discussionmentioning

confidence: 91%

“…Production of Free 125/-during Degradation. Deiodinase(s) in hepatocytes catalyze(s) the formation of free 125 during the catabolism of 125I-labeled lipoproteins Pangburn et al, 1981), and it was considered that direct deiodination of the labeled lipoproteins may produce errors in the degradation measurements. We found that 90% of the Cl3CCOOH-soluble radioactivity produced from 125I-HDL and about 85% of that produced from 125I-LDL were present in the form of free 125 .…”

Section: Resultsmentioning

confidence: 99%

“…High-affinity uptake and degradation of LDL have been observed in suspended rat (Van Berkel et al, 1980;Ose et al, 1980a) and rabbit hepatocytes (Soltys & Portman, 1979). Pangburn et al (1981) recently presented evidence in cultured swine hepatocytes for the degradation of 125I-LDL by an LDL receptor mediated mechanism. The mechanisms by which the apoproteins of HDL are catabolized and the role of the liver in this process are unclear.…”

mentioning

confidence: 99%

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High-affinity uptake and degradation of ApoE-free high-density lipoprotein and low-density lipoprotein in cultured porcine hepatocytes

et al. 1982

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Isolated pig liver membranes contain a specific "lipoprotein binding site" that recognizes low-density lipoproteins (LDL) and apolipoprotein E (apoE) free high-density lipoprotein (HDL) [Bachorik, P. S., Kwiterovich, P. O., & Cooke, J. (1978) Biochemistry 17, 5287-5299]. We report here that a similar site exists in cultured porcine hepatocytes and that it mediates the uptake and degradation of apoE-free HDL. The binding of 125I-labeled HDL and 125I-labeled LDL (125I-HDL and 125I-LDL, respectively) at 4 degrees C and the uptake and degradation of the lipoproteins at 37 degrees C were time dependent and saturable and were not inhibited by unrelated proteins. Chloroquine (6 x 10(-5)M) inhibited the degradation of 125I-HDL by 76% and of 125I-LDL by greater than 99%; leupeptin inhibited the degradation of both lipoproteins by about 25%. 125I-HDL binding (4 degrees C), uptake, and degradation (37 degrees C) were inhibited by LDL, methyl-LDL, and methyl-HDL about as well as by unlabeled HDL but were unaltered in Pronase-treated cells or in cells that were cultured for 24 h in either lipoprotein-free medium containing HDL or LDL (200 micrograms/mL). In contrast, these conditions affected the uptake and degradation of 125I-LDL disproportionately. HDL and methyl-LDL inhibited 125I-LDL uptake by 50% or more but had little effect on degradation. 125I-LDL binding was reduced by 12% and degradation by 57% in Pronase-treated cells. Preincubation of the cells with LDL (200 micrograms/mL) reduced uptake by 35% and degradation by 68%. Similar preincubation with HDL (200 micrograms/mL) increased 125I-LDL degradation by 60% but did not affect 125I-LDL uptake. The findings indicated the presence in porcine hepatocytes of at least two distinct sites for lipoproteins. One site resembled the LDL receptor and mediated 125I-LDL degradation. A second, Pronase-insensitive site recognized both HDL and LDL. This site mediated almost all of the degradation of 125I-HDL but little if any degradation of 125I-LDL.

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Section: Discussionsupporting

confidence: 87%

Section: Resultssupporting

confidence: 56%

Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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High-affinity uptake and degradation of ApoE-free high-density lipoprotein and low-density lipoprotein in cultured porcine hepatocytes

et al. 1982

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Modulation of hepatic and extrahepatic LDL receptors: Involvement in the progression of atherosclerosis

Newton¹

1985

Drug Development Research

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Newton, R.S.: Modulation of hepatic and extrahepatic LDL receptors: ltivolvement in the progression of atherosclerosis. Drug Dev. Res.6:141-154, 1985. Extensive investigation over the past 2 decades has led to a far better understanding of the role of lipoproteins in the etiology and progression of atherosclerosis. Paramount to this understanding has been the elucidation of how cells recognize these macromolecular complexes and metabolize the lipids and proteins they transport. Because of their elevation in plasma of many individuals with premature coronary heart disease, low-density lipoproteins (LDL) have received particular attention. As primary transporters of cholesterol to cells in mammalian tissues, LDL particles are removed from blood via specific cell surface receptors that facilitate their uptake. Once internalized and exposed to lysosomal enzymes, LDL particles are degraded, "freeing" their cholesterol to regulate cellular cholesterol synthesis and modulate the number of LDL receptors on the cell membrane. This high-affinity, high-capacity process has been termed the LDL receptor pathway and is functional in most tissues of the body, especially in liver where over 50°/o of the total body LDL degradation occurs. Liver is the target organ of bile acid sequestrants (cholestyraminelcolestipol) and HMG-CoA reductase inhibitors (compactinlmevinolin), both of which induce increased expression of LDL receptors by affecting hepatic cholesterol availability. Unlike liver, the arterial wall under normal conditions is not very active at degrading LDL via the classical LDL receptor pathway. However, when hypercholesterolemia occurs, especially when there is an LDL-receptor deficiency, the arterial wall removes 20-fold more LDL than normal and with a greater fractional catabolic rate. Thus other endocytotic pathways exist by which LDL can enter cells of the arterial wall. These pathways are not as acutely regulated as the classical LDL receptor pathway, and, as a result, the arterial wall cells, particularly smooth muscle cells and resident macrophages, accumulate cholesteryl esters. In this brief review, the importance of these receptors to the etiology and progression of atherosclerosis is discussed in detail and sites of possible pharmacological intervention are identified.

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Hepatic Catabolism of Low Density Lipoprotein: Mechanisms and Metabolic Consequences

2007

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The purpose of this short review is to summarize information currently available about the extent to which the liver takes up and degrades low-density lipoprotein (LDL), the mechanism of uptake, and its metabolic consequences. One reason for a review on this narrowly defined topic is recent evidence establishing that the liver in most animals probably accounts for more than 50% of total body LDL degradation, as will be discussed in detail. The corollary of that finding is that regulation of hepatic degradation may, therefore, be crucial in determining steady-state plasma levels of LDL. Indeed, it is already clear that some drugs act to lower LDL levels by regulating hepatic LDL receptor number. A second reason for choosing to review hepatic LDL catabolism is that studies of cultured hepatocytes are beginning to shed light on alternative, low-affinity pathways for LDL uptake; these pathways may have different metabolic consequences than uptake via specific, receptor-mediated pathways. Before discussing LDL catabolism, however, it may be useful to place it in context by briefly reviewing the overall participation of the liver in lipoprotein metabolism. HEPATIC LIPOPROTEIN METABOLISM:A CAPSULE VIEW The liver is the major source of plasma lipoproteins, secreting mainly very low-density lipoproteins (VLDL) and high-density lipoproteins (HDL). The intestine can also synthesize and secrete these lipoproteins in addition to its major contribution, the chylomicrons. But the intestinal contribution to VLDL and HDL production is probably much less than that of the liver.

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Receptor-mediated catabolism of homologous low density lipoproteins in cultured pig hepatocytes.

Cited by 88 publications

References 48 publications

High-affinity uptake and degradation of ApoE-free high-density lipoprotein and low-density lipoprotein in cultured porcine hepatocytes

High-affinity uptake and degradation of ApoE-free high-density lipoprotein and low-density lipoprotein in cultured porcine hepatocytes

Modulation of hepatic and extrahepatic LDL receptors: Involvement in the progression of atherosclerosis

Hepatic Catabolism of Low Density Lipoprotein: Mechanisms and Metabolic Consequences

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