Increased fatty acid desaturation and enhanced expression of stearoyl coenzyme A desaturase protects pancreatic beta-cells from lipoapoptosis.
Increased availability of fatty acids causes cell death and dysfunction in beta-cell lines, isolated islets, and animal models of diabetes. From the MIN6 beta-cell line, we selected two subpools that are resistant to palmitate-induced apoptosis. Protection was not universal because palmitate-resistant cells remained sensitive to cytokine- and streptozotocin-induced apoptosis. Palmitate oxidation and incorporation into cholesterol ester (but not triglycerides) were significantly higher in palmitate-resistant cells than in control cells. Consistent with these findings, transcript profiling revealed increased expression in palmitate-resistant cells of several beta-oxidation genes as well as a 2.8-fold upregulation of stearoyl-CoA desaturase 1 (SCD1). Correspondingly, the oleate-to-palmitate ratio of palmitate-resistant cells was double that of palmitate-pretreated control cells. At least some of this additional oleate in palmitate-resistant cells was incorporated into cholesterol ester stored in the form of large cytosolic lipid bodies. However, blocking cholesterol ester formation did not render palmitate-resistant cells sensitive to palmitate-induced apoptosis. On the other hand, an inhibitor of SCD1, 10,12-conjugated linoleic acid, dose dependently overcame the resistance of palmitate-resistant cells to lipoapoptosis. Our results suggest that desaturation per se is more important in protecting beta-cells from the cytotoxic effects of palmitate than is the nature of neutral lipid storage pool thus generated.
Busch
Anna K
AK
Garvan Institute of Medical Research, St.Vincent's Hospital, Sydney 2010, Australia.
Gurisik
Ebru
E
Cordery
Damien V
DV
Sudlow
Michelle
M
Denyer
Gareth S
GS
Laybutt
D Ross
DR
Hughes
William E
WE
Biden
Trevor J
TJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002788:Cholesterol Esters / Q000378:metabolism; D004351:Drug Resistance; D044943:Fatty Acid Desaturases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology*; D008055:Lipids / Q000032:analysis; D051379:Mice; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D002788:Cholesterol Esters; D005227:Fatty Acids; D008055:Lipids; D014280:Triglycerides; D019308:Palmitic Acid; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase