Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic beta cells.
OBJECTIVE
We explored the potential adverse effects of pro-atherogenic oxidised LDL-cholesterol particles on beta cell function.


METHODS
Isolated human and rat islets and different insulin-secreting cell lines were incubated with human oxidised LDL with or without HDL particles. The insulin level was monitored by ELISA, real-time PCR and a rat insulin promoter construct linked to luciferase gene reporter. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei.


RESULTS
Prolonged incubation with human oxidised LDL particles led to a reduction in preproinsulin expression levels, whereas the insulin level was preserved in the presence of native LDL-cholesterol. The loss of insulin production occurred at the transcriptional levels and was associated with an increase in activator protein-1 transcriptional activity. The rise in activator protein-1 activity resulted from activation of c-Jun N-terminal kinases (JNK, now known as mitogen-activated protein kinase 8 [MAPK8]) due to a subsequent decrease in islet-brain 1 (IB1; now known as MAPK8 interacting protein 1) levels. Consistent with the pro-apoptotic role of the JNK pathway, oxidised LDL also induced a twofold increase in the rate of beta cell apoptosis. Treatment of the cells with JNK inhibitor peptides or HDL countered the effects mediated by oxidised LDL.


CONCLUSIONS
These data provide strong evidence that oxidised LDL particles exert deleterious effects in the progression of beta cell failure in diabetes and that these effects can be countered by HDL particles.
Abderrahmani
A
A
Service of Internal Medicine, CHUV-Hospital, Rue du Bugnon 9, 1005 Lausanne, Switzerland. Amar.Abderrahmani@unil.ch
Niederhauser
G
G
Favre
D
D
Abdelli
S
S
Ferdaoussi
M
M
Yang
J Y
JY
Regazzi
R
R
Widmann
C
C
Waeber
G
G
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003920:Diabetes Mellitus / Q000201:enzymology; D018450:Disease Progression; D004789:Enzyme Activation; D017930:Genes, Reporter; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D012313:RNA; D048670:MAP Kinase Kinase 4