Journal of Lipid Research, Vol 23, 984-993, Copyright © 1982 by Lipid Research, Inc.

ARTICLES

Receptor-mediated uptake of hypertriglyceridemic very low density lipoproteins by normal human fibroblasts

SH Gianturco, FB Brown, AM Gotto Jr and WA Bradley

Our previous studies showed that very low density lipoproteins, Sf 60- 400 (VLDL), from hypertriglyceridemia subjects, but not VLDL from normolipemic subjects, suppress HMG-CoA reductase activity in normal human fibroblasts. To determine if this functional abnormality of hypertriglyceridemic VLDL resulted from differences in uptake of the VLDL by the low density lipoprotein (LDL) receptor pathway, we isolated VLDL subclasses from the d less than 1.006 g/ml fraction of normal and hypertriglyceridemic plasma by flotation through a discontinuous salt gradient for direct and competitive binding studies in cultured human fibroblasts. VLDL from the plasma of subjects with hypertriglyceridemia types 4 and 5 were at least as effective as normal LDL in competing for 125I-labeled LDL binding, uptake, and degradation when compared either on the basis of protein content or on a particle basis. By contrast, normolipemic Sf 60-400 VLDL were ineffective in competing with the degradation of 125I-labeled LDL, and Sf 20-60 VLDL (VLDL3) were less effective in reducing specific 125I-labeled LDL degradation than were LDL, consistent with their effects on HMG-CoA reductase activity. In direct binding studies, radiolabeled VLDL from hypertriglyceridemic but not normolipemic subjects were bound, internalized, and degraded with high affinity and specificity by normal fibroblasts. Uptake and degradation of iodinated hypertriglyceridemic VLDL Sf 100-400 showed a saturable dependence on VLDL concentration. Specific degradation plateaued at approximately 25 micrograms VLDL protein/ml, with a half maximal value at 6 micrograms/ml. The most effective competitor of hypertriglyceridemic VLDL uptake and degradation was hypertriglyceridemic VLDL itself. LDL were effective only at high concentrations. Uptake of normal VLDL by normal cells was a linear rather than saturable function of VLDL concentration. By contrast, cellular uptake of the smaller normal VLDL3 was greater than uptake of larger VLDL and showed saturation dependence. After incubation of normal VLDL with 125I-labeled apoprotein E, reisolated 125I-E-VLDL were as effective as LDL in suppression of HMG-CoA reductase activity, suggesting that apoE is involved in receptor-mediated uptake of large suppressive VLDL. We conclude that 1) hypertriglyceridemic VLDL Sf 60- 400 are bound, internalized, and degraded by normal fibroblasts primarily by the high affinity LDL receptor-mediated pathway; 2) by contrast, normal VLDL, Sf 60-400 are bound, internalized, and degraded by normal fibroblasts primarily by nonspecific, nonsaturable routes; and 3) of the normal VLDL subclasses, only the smallest Sf 20-60 fraction is bound and internalized via the LDL pathway.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. G. Jackson, V. Maitin, D. S. Leake, P. Yaqoob, and C. M. Williams Saturated fat-induced changes in Sf 60-400 particle composition reduces uptake of LDL by HepG2 cells J. Lipid Res., February 1, 2006; 47(2): 393 - 403. [Abstract] [Full Text] [PDF]

				I. Grosskopf, N. Baroukh, S.-J. Lee, Y. Kamari, D. Harats, E. M. Rubin, L. A. Pennacchio, and A. D. Cooper Apolipoprotein A-V Deficiency Results in Marked Hypertriglyceridemia Attributable to Decreased Lipolysis of Triglyceride-Rich Lipoproteins and Removal of Their Remnants Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2573 - 2579. [Abstract] [Full Text] [PDF]

				A. Schlitt, M. R. Hojjati, H. von Gizycki, K. J. Lackner, S. Blankenberg, B. Schwaab, J. Meyer, H. J. Rupprecht, and X.-C. Jiang Serum sphingomyelin levels are related to the clearance of postprandial remnant-like particles J. Lipid Res., February 1, 2005; 46(2): 196 - 200. [Abstract] [Full Text] [PDF]

				G. Datta, D. W. Garber, B. H. Chung, M. Chaddha, N. Dashti, W. A. Bradley, S. H. Gianturco, and G. M. Anantharamaiah Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo J. Lipid Res., June 1, 2001; 42(6): 959 - 966. [Abstract] [Full Text]

				S. C. Whitman, S. L. Hazen, D. B. Miller, R. A. Hegele, J. W. Heinecke, and M. W. Huff Modification of Type III VLDL, Their Remnants, and VLDL From ApoE-Knockout Mice by p-Hydroxyphenylacetaldehyde, a Product of Myeloperoxidase Activity, Causes Marked Cholesteryl Ester Accumulation in Macrophages Arterioscler. Thromb. Vasc. Biol., May 1, 1999; 19(5): 1238 - 1249. [Abstract] [Full Text] [PDF]

				J. R. Burnett, P. H. R. Barrett, P. Vicini, D. B. Miller, D. E. Telford, S. J. Kleinstiver, and M. W. Huff The HMG-CoA Reductase Inhibitor Atorvastatin Increases the Fractional Clearance Rate of Postprandial Triglyceride-Rich Lipoproteins in Miniature Pigs Arterioscler. Thromb. Vasc. Biol., December 1, 1998; 18(12): 1906 - 1914. [Abstract] [Full Text] [PDF]

				J. Björkegren, F. Karpe, R. W. Milne, and A. Hamsten Differences in apolipoprotein and lipid composition between human chylomicron remnants and very low density lipoproteins isolated from fasting and postprandial plasma J. Lipid Res., July 1, 1998; 39(7): 1412 - 1420. [Abstract] [Full Text]

				S. H. Gianturco, M. P. Ramprasad, R. Song, R. Li, M. L. Brown, and W. A. Bradley Apolipoprotein B-48 or Its Apolipoprotein B-100 Equivalent Mediates the Binding of Triglyceride-Rich Lipoproteins to Their Unique Human Monocyte-Macrophage Receptor Arterioscler. Thromb. Vasc. Biol., June 1, 1998; 18(6): 968 - 976. [Abstract] [Full Text] [PDF]

				J. Björkegren, F. Karpe, S. Vitols, P. Tornvall, and A. Hamsten Transient triglyceridemia in healthy normolipidemic men increases cellular processing of large very low density lipoproteins by fibroblasts in vitro J. Lipid Res., February 1, 1998; 39(2): 423 - 437. [Abstract] [Full Text]