Identification of ALOX5 as a gene regulating adiposity and pancreatic function.
OBJECTIVE
We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 (-/-)) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function.


METHODS
Alox5 (-/-) and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments.


RESULTS
Beginning at 12 weeks of age, Alox5 (-/-) mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p<0.05). Although Alox5 (-/-) mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed that Alox5 (-/-) mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm(2) islet (p<0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 (-/-) islets were significantly lower than in WT islets (p<0.05) and accompanied by a three- to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05).


CONCLUSIONS
These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.
Mehrabian
M
M
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Schulthess
F T
FT
Nebohacova
M
M
Castellani
L W
LW
Zhou
Z
Z
Hartiala
J
J
Oberholzer
J
J
Lusis
A J
AJ
Maedler
K
K
Allayee
H
H
D058927:5-Lipoxygenase-Activating Proteins; D000273:Adipose Tissue / Q000201:enzymology* / Q000502:physiology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D001835:Body Weight; D002352:Carrier Proteins / Q000235:genetics*; D003433:Crosses, Genetic; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000201:enzymology*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012727:Sex Characteristics; D014019:Tissue Donors
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D020738:Leptin; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D012313:RNA; D001094:Arachidonate 5-Lipoxygenase