Arteriosclerosis, Vol 9, 501-510, Copyright © 1989 by American Heart Association

ARTICLES

Beta-very low density lipoprotein uptake in cultured fibroblasts and smooth muscle cells from Watanabe heritable hyperlipidemic rabbits

ME Wernette-Hammond, Z Garcia, KS Arnold and TL Innerarity
Gladstone Foundation Laboratories for Cardiovascular Disease, University of California, San Francisco 94140.

Watanabe Heritable Hyperlipidemic (WHHL) rabbits are an important animal model used to study the effects of defective low density lipoprotein (LDL) receptors on lipoprotein metabolism. In the present study, the receptor-mediated catabolism of apolipoprotein (apo) E- containing lipoproteins was investigated in fibroblasts and smooth muscle cells cultured from WHHL rabbits. Fibroblasts from WHHL rabbits bound little, if any, human LDL, an apo B-containing lipoprotein, in 4 degrees C equilibrium binding experiments. In contrast, canine beta- very low density lipoproteins (beta-VLDL), which contain apo E, bound to these cells with an affinity similar to that for fibroblasts of normal New Zealand White rabbits (Kd approximately 0.6 micrograms/ml), although the maximal binding was only approximately 9% of that of New Zealand White cells. At 37 degrees C, beta-VLDL were degraded efficiently by WHHL fibroblasts, that is, at rates approximately half of that for New Zealand White fibroblasts. The degradation of beta-VLDL by WHHL fibroblasts was blocked by reductive methylation of the lipoproteins and was inhibited by the anti-apo E monoclonal antibody, 1D7. Unlike human LDL, canine beta-VLDL induced 14C-oleate incorporation into cholesteryl esters in WHHL fibroblasts and smooth muscle cells. The uptake of beta-VLDL by WHHL cells was mediated by the LDL receptor, since preincubation of the fibroblasts with cholesterol plus 25-hydroxycholesterol inhibited beta-VLDL degradation, and specific antibodies to rabbit LDL receptors abolished the degradation of beta-VLDL in WHHL fibroblasts. These results indicate that the altered LDL receptors expressed on cultured WHHL rabbit cells are sufficient for apo E-dependent, receptor-mediated uptake of lipoproteins. Thus, the altered LDL receptors could contribute to in vivo metabolism of apo E-containing lipoproteins despite their lack of LDL binding activity.

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