Phagocytic degradation of chylomicron remnants by fibroblasts from subjects with homozygous familial hypercholesterolaemia.
1. Familial hypercholesterolaemia is a common genetic abnormality in man characterized by premature atherogenesis as a consequence of disturbed lipoprotein metabolism. Chylomicrons, which represent intestinally derived lipoproteins, are cleared poorly in familial hypercholesterolaemia which may explain the increased retention of chylomicron remnants in arterial fatty lesions. However, cellular uptake of chylomicron remnants in familial hypercholesterolaemia remains unclear. This study determined the quantitative significance of non-low-density lipoprotein receptor-mediated uptake in fibroblasts from subjects with homozygous familial hypercholesterolaemia. 2. The metabolism of chylomicron remnants was assessed in fibroblasts from subjects with homozygous familial hypercholesterolaemia who lack low-density lipoprotein receptors. Compared with fibroblasts from normolipidaemic subjects, binding and degradation of chylomicron remnants was reduced by about two-thirds. Nevertheless, degradation of chylomicron remnants in cells from subjects with familial hypercholesterolaemia persisted in the absence of functioning low-density lipoprotein receptors. 3. Binding of chylomicron remnants to fibroblasts from subjects with familial hypercholesterolaemia was saturable. Unlabelled chylomicron remnants competed efficiently for binding but unlabelled low-density lipoprotein or a monoclonal antibody specific to the human low-density lipoprotein receptor had little effect on binding or degradation. 4. Polyinosinic acid did not alter binding and degradation of chylomicron remnants by fibroblasts from subjects with familial hypercholesterolaemia, ruling out involvement of the scavenger receptor. Lactoferrin was found to inhibit binding and degradation of chylomicron remnants by fibroblasts from subjects with familial hypercholesterolaemia by approximately 50%, implicating involvement of the alpha 2-macroglobulin receptor. 5. Cytochalasin D blocked degradation of chylomicron remnants at 37 degrees C in fibroblasts from subjects with familial hypercholesterolaemia by more than 80% but had no effect on binding at 4 degrees C, consistent with a phagocytic uptake pathway. Collectively, the data suggest that chylomicron remnants bind to a cell-surface protein which initiates phagocytosis and that lactoferrin interferes with binding to this putative cell-surface protein. Phagocytic uptake of chylomicron remnants provides an additional mechanism whereby cells from subjects with familial hypercholesterolaemia can accumulate lipid.
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Department of Physiology, University of Western Australia, Perth, Australia.
Smith
D
D
Yamamoto
A
A
Kawaguchi
A
A
Harada-Shiba
M
M
Yamamura
T
T
Mamo
J C
JC
D000328:Adult; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D002914:Chylomicrons / Q000378:metabolism*; D015638:Cytochalasin D / Q000494:pharmacology; D005347:Fibroblasts / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism / Q000473:pathology*; D007457:Iodine Radioisotopes; D007781:Lactoferrin / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008565:Membrane Proteins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D011069:Poly I / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D011973:Receptors, LDL / Q000378:metabolism; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D012867:Skin / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014439:Tyramine / Q000378:metabolism
D002273:Carcinogens; D002914:Chylomicrons; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D015638:Cytochalasin D; D011069:Poly I; D007781:Lactoferrin; D013755:Tetradecanoylphorbol Acetate; D014439:Tyramine