Abstract
The low-density lipoprotein (LDL) receptor plays a crucial role in cholesterol metabolism. A related protein, designated the very low density lipoprotein (VLDL) receptor, that specifically binds apolipoprotein (apo) E has recently been characterized and shown to be expressed in heart, muscle and adipose tissue and the human monocyte-macrophage cell line THP-1. The VLDL receptor binds and internalizes VLDL and intermediate density lipoprotein from Watanabe heritable hyperlipidemic (WHHL) rabbits as well as beta-migrating VLDL from cholesterol-fed rabbits but not LDL from WHHL rabbits. Chinese hamster ovary (CHO) cells transfected with the rabbit VLDL receptor cDNA have now been shown to bind or internalize VLDL (d < 1.006 g/ml) isolated from fasted normolipidemic human subjects with lower affinity than WHHL-VLDL or rabbit beta-VLDL. However, binding and internalization were markedly enhanced when fasted human VLDL was preincubated with either recombinant human apoE (3/3) or lipoprotein lipase (LPL) in CHO cells overexpressing the rabbit or human VLDL receptor. CHO cells transfected with both the rabbit VLDL receptor cDNA and the human LPL cDNA effectively bound, internalized, and degraded fasted human VLDL without pretreatment. Treatment of heparinase reduced the effect of LPL-mediated binding at 4 degrees C, but the inhibitory effect was lower at 37 degrees C. Pseudomonas LPL also enhanced the binding of human fasted VLDL to the VLDL receptor at 37 degrees C in CHO cells overexpressing the human VLDL receptor. Taken together, LPL causes the enhancement of triglyceride-rich lipoproteins binding to the VLDL receptor via both the formation of bridge between lipoproteins and heparan sulfate proteoglycans and its lipolytic effect. Ligand blot analysis showed that the apparent molecular mass of the VLDL receptor is 118 kDa, which is smaller than that of the LDL receptor. These results indicate that the VLDL receptor recognizes both triglyceride-rich lipoproteins that are also relatively rich in apoE, as well as the remnants of triglyceride-rich lipoproteins after catabolism and the interaction with heparan sulfate proteoglycans by LPL. The VLDL receptor may thus function as a receptor for remnants of triglyceride-rich lipoproteins in extrahepatic tissues.
Highlights
From the Third Department of Internal Medicine, Fukui Medical School, Fukui 910-11, Japan and the §Tohoku University Gene Research Center, Sendai 981, Japan
We recently demonstrated that /3-very low density lipoprotein (VLDL) obtained from the plasma of cholesterol-fed rabbits induces foam cell formation in Chinese hamster ovary cells transfected with the rabbit VLDL receptor eDNA and that the cholesteryl esters of /3-VLDL particles are hydrolyzed within cellular lysosomes [17]
Effects of ApoE- We have previously shown that the rabbit VLDL receptor binds and internalizes VLDL (d < 1.006 g!ml) and intermediate density lipoprotein (IDL) (1.006 g/ml < d < 1.019 g/ml) from Watanabe heritable hyperlipidemic (WHHL) rabbits as well as {3-VLDL (d < 1.006 g/ml) from cholesterol-fed rabbits with high affinity but not low-density lipoprotein (LDL) (1.019 < d < 1.063 g/ml) from WHHL rabbits [2, 3]
Summary
Vol 270, No 26, Issue of June 30, pp. 15747-15754, 1995 Printed in U.S.A. Enhancement of the Binding of Triglyceride-rich Lipoproteins to the Very Low Density Lipoprotein Receptor by Apolipoprotein E and Lipoprotein Lipase*. A related protein, designated the very low density lipoprotein (VLDL) receptor, that binds apolipoprotein (apo) E has recently been characterized and shown to be expressed in heart, muscle and adipose tissue and the human monocyte-macrophage cell line THP-1. Northern blot analysis revealed the presence of VLDL receptor mRNA in rabbit resident alveolar macrophages, and the mRNA was not down-regulated by /3-VLDL [17] These observations suggest that macrophages take up triglyceride-rich lipoproteins via the VLDL receptor and are transformed into foam cells. We have examined the effects of apoE and LPL on the uptake of triglyceride-rich lipoproteins via the VLDL receptor in Chinese hamster ovary cells and clarified the apparent molecular mass of the VLDL receptor by ligand blotting
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