Human LDL receptor enhances sequestration of ApoE4 and VLDL remnants on the surface of hepatocytes but not their internalization in mice.
OBJECTIVE
In humans, apolipoprotein (apo) E4 is associated with elevated plasma cholesterol levels and a high risk of developing atherosclerosis, whereas apoE2 is protective. Here we investigate the mechanism by which mice expressing human apoE isoforms recapitulate this association when they also express high levels of human low-density lipoprotein receptor (LDLR).


RESULTS
Primary hepatocytes from apoE4 mice secreted less apoE into the medium than hepatocytes from apoE2 mice. Increased LDLR expression decreased this secretion and increased degradation of apoE4. An apoE4-GFP fusion protein expressed in the liver of apoE-deficient mice accumulated on the hepatocyte surface bordering the space of Disse in an LDLR-dependent manner. Fluorescence-labeled very low-density lipoprotein (VLDL) remnants accumulated on the hepatocyte surface in apoE4 mice with high LDLR, but they were internalized poorly. In contrast, apoE2-GFP did not accumulate on the hepatocyte surface even when the LDLR expression was high, but apoE2 mice with high LDLR internalized the remnants avidly without sequestering them on the hepatocyte surface.


CONCLUSIONS
The high affinity of apoE4 to the LDLR enhances VLDL sequestration on the hepatocyte surface but delays their internalization. This delay likely increases VLDL conversion to cholesterol-enriched remnants in apoE4 mice with high LDLR, and probably to LDL in humans with apoE4.
Altenburg
Michael
M
Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525, USA.
Arbones-Mainar
Jose
J
Johnson
Lance
L
Wilder
Jennifer
J
Maeda
Nobuyo
N
D000256:Adenoviridae / Q000235:genetics; D000483:Alleles; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics / Q000378:metabolism; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015243:Cholesterol, VLDL / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D015243:Cholesterol, VLDL; D020033:Protein Isoforms; D011973:Receptors, LDL