© 1996 American Heart Association, Inc.
Articles |
Differences in Receptor Binding of LDL Subfractions
From the Donner Laboratory, University of California, and the Department of Molecular and Nuclear Medicine, Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley (H.C., R.M.K.), and the Gladstone Institute of Cardiovascular Disease, San Francisco (K.S.A., M.E.B., T.L.I.), California.
Correspondence to Ronald M. Krauss, MD, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Donner Laboratory Room 465, One Cyclotron Rd, Berkeley, CA 94720. E-mail rmkrauss@lbl.gov.
Abstract Differences in low density lipoprotein (LDL)
receptor-binding affinity among LDL particles of different size
were examined in competitive binding assays in human skin fibroblasts
and LDL (d=1.020 to 1.050 g/mL) from subjects with a
predominance of large (
272 Å), medium (259 to 271 Å), and small
(
257 Å) LDL. Among 57 normolipidemic subjects with LDL
cholesterol (-C) levels <160 mg/dL, binding affinity was
reduced by 16% in those with predominantly large LDL and by 14% in
those with small LDL compared with most subjects who had a predominance
of medium-size LDL and in all LDL size subgroups in 66 subjects
with LDL-C 160 mg/dL. Differences in LDL receptor-binding
affinity were further investigated by using LDL density subfractions
(I, d=1.026 to 1.032 g/mL; II, d=1.032 to 1.038
g/mL; and III, d=1.038 to 1.050 g/mL) from three subjects
with predominantly large (pattern A) and small (pattern B) LDL
particles. The binding affinity (Kd) of LDL-II
was similar for patterns A and B (9.2±1.4 and 9.4±0.7, respectively)
and 30% lower in LDL-III from both groups (P<.05). The
binding affinity of LDL-I in pattern A (12.6±1.5 µg/mg) was lower
(P<.05) than that in LDL-II and LDL-I from pattern B
(8.0±2.4 µg/mg). After incubation with a monoclonal antibody that
specifically blocked the LDL receptor-binding domain of apoE, LDL-I
from two pattern B subjects showed substantially lower binding affinity
(Kd=20.0 and 19.2 µg/mg) than in pattern A
(Kd=13.2 and 14.2 µg/mg), a result
consistent with our finding of a higher apoE content in pattern
B LDL-I (P<.001). Thus, factors associated with variations
in particle size and apoE content in LDL subclasses in normolipidemic
subjects contribute to the differences in LDL receptor binding that may
result in differing metabolic behavior in vivo.
Key Words: LDL subclasses • LDL size • apoE • LDL receptor • cholesterol
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