Low density lipoprotein can cause death of islet beta-cells by its cellular uptake and oxidative modification.
Islet beta-cells express receptors for low density (LDL) and very low density (VLDL) lipoproteins that are internalized by receptor-mediated endocytosis. The present study examined whether this process can affect the viability of isolated rat islet beta-cells. Culture with LDL (from 6 micro g/ml on), but not VLDL, causes necrosis of beta-cells within 2 d. No toxicity was observed when LDL binding and/or endocytosis was prevented by low temperature (8 C), or by addition of heparin or an excess of VLDL. The LDL toxicity did not occur in the presence of antioxidants (probucol or a mixture of glutathion, vitamins A, C, E plus dithiothreitol) or of the radical scavenger butylated hydroxytoluene. The degree of LDL-induced toxicity was correlated with an increase in the electrophoretic mobility of LDL, an index for its oxidative modification. Both LDL toxicity and oxidation were suppressed by omission or chelation of copper and iron in the medium. Addition of oxidized LDL was not cytotoxic to beta-cells, which lack oxidized LDL receptors. It is concluded that uptake of LDL by islet beta-cells and subsequent oxidative reactions can be damaging for the cells. This process can be counteracted by HDL and VLDL, and by antioxidants.
Diabetes Research Center, Brussels Free University--Vrije Universiteit Brussel, Brussels 1090, Belgium.
Miriam
M
Cnop
Jean Claude
JC
Hannaert
Annick Y
AY
Grupping
Daniel G
DG
Pipeleers
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001562:Benzimidazoles; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003080:Cold Temperature; D003300:Copper / Q000737:chemistry; D004229:Dithiothreitol / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D005456:Fluorescent Dyes; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000737:chemistry; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry
D000975:Antioxidants; D001562:Benzimidazoles; D005456:Fluorescent Dyes; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D014801:Vitamin A; D014810:Vitamin E; D009569:Nitric Oxide; D003300:Copper; D006493:Heparin; D007501:Iron; D015032:Zinc; C017807:bisbenzimide ethoxide trihydrochloride; D001205:Ascorbic Acid; D004229:Dithiothreitol