Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARalpha-dependent stearoyl-coenzyme A desaturase.
Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARalpha-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRbeta(-/-) and LXRalphabeta(-/-)), beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARalpha agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARalpha agonists favors their desaturation and subsequent incorporation in neutral lipids.
Hellemans
Karine H
KH
Diabetes Research Center, Brussels Free University-VUB, and JDRF Center for Beta Cell Therapy in Diabetes, Brussels, Belgium. karine.hellemans@vub.ac.be
Hannaert
Jean-Claude
JC
Denys
Bart
B
Steffensen
Knut R
KR
Raemdonck
Cindy
C
Martens
Geert A
GA
Van Veldhoven
Paul P
PP
Gustafsson
Jan-Ake
JA
Pipeleers
Daniel
D
D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D050356:Lipid Metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D010169:Palmitic Acids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D010169:Palmitic Acids; D014280:Triglycerides; D013230:Stearoyl-CoA Desaturase