Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells.
A low high-density lipoprotein (HDL) plasma concentration and the abundance of small dense low-density lipoproteins (LDL) are risk factors for developing type 2 diabetes. We therefore investigated whether HDL and LDL play a role in the regulation of pancreatic islet cell apoptosis, proliferation, and secretory function. Isolated mouse and human islets were exposed to plasma lipoproteins of healthy human donors. In murine and human beta-cells, LDL decreased both proliferation and maximal glucose-stimulated insulin secretion. The comparative analysis of beta-cells from wild-type and LDL receptor-deficient mice revealed that the inhibitory effect of LDL on insulin secretion but not proliferation requires the LDL receptor. HDL was found to modulate the survival of both human and murine islets by decreasing basal as well as IL-1beta and glucose-induced apoptosis. IL-1beta-induced beta-cell apoptosis was also inhibited in the presence of either the delipidated protein or the deproteinated lipid moieties of HDL, apolipoprotein A1 (the main protein component of HDL), or sphingosine-1-phosphate (a bioactive sphingolipid mostly carried by HDL). In murine beta-cells, the protective effect of HDL against IL-1beta-induced apoptosis was also observed in the absence of the HDL receptor scavenger receptor class B type 1. Our data show that both LDL and HDL affect function or survival of beta-cells and raise the question whether dyslipidemia contributes to beta-cell failure and hence the manifestation and progression of type 2 diabetes mellitus.
Rütti
Sabine
S
Division of Endocrinology and Diabetes, University Hospital of Zürich, Zurich 8091, Switzerland.
Ehses
Jan A
JA
Sibler
Rahel A
RA
Prazak
Richard
R
Rohrer
Lucia
L
Georgopoulos
Spiros
S
Meier
Daniel T
DT
Niclauss
Nadja
N
Berney
Thierry
T
Donath
Marc Y
MY
von Eckardstein
Arnold
A
D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000502:physiology*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D016632:Apolipoprotein A-I; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C491899:Fas protein, mouse; D007328:Insulin; D053583:Interleukin-1beta; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D011973:Receptors, LDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D019014:fas Receptor; C060506:sphingosine 1-phosphate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005947:Glucose; D013110:Sphingosine