Induction of stearoyl-CoA desaturase protects human arterial endothelial cells against lipotoxicity.
Endothelial lipotoxicity has been implicated in the pathogenesis of multiple stages of cardiovascular disease from early endothelial dysfunction to manifest atherosclerosis and its complications. Saturated free fatty acids are the major inducers of endothelial cell apoptosis and inflammatory cytokines. In humans, the enzyme human stearoyl-CoA desaturase-1 (hSCD-1) is the limiting step of the desaturation of saturated to monounsaturated fatty acids. Since we could demonstrate the expression of SCD-1 in primary human arterial endothelial cells (HAECs), we aimed to prove a beneficial role of upregulated hSCD-1 expression. In contrast to other cells that are less susceptible to lipotoxicity, hSCD-1 was not upregulated in HAECs upon palmitate treatment. Following that, we could show that upregulation of hSCD-1 using the LXR activator TO-901317 in HAECs protects the cells against palmitate-induced lipotoxicity, cell apoptosis, and expression of inflammatory cytokines IL-6 and IL-8. Increased hSCD-1 activity was determined as increased C16:1/16:0 ratio and enhanced triglyceride storage in palmitate treated cells. The beneficial effect was clearly attributed to enhanced hSCD-1 activity. Overexpression of hSCD-1 blocked palmitate-induced cytotoxicity, and knockdown of hSCD-1 using siRNA abolished the protective effect of TO-901317 in HEK-293 cells. Additionally, inhibition of hSCD-1 with 10/12 CLA blocked the effect of TO-901317 on palmitate-induced lipotoxicity, cell apoptosis, and inflammatory cytokine induction in HAECs. We conclude that upregulation of hSCD-1 leads to a desaturation of saturated fatty acids and facilitates their esterification and storage, thereby preventing downstream effects of lipotoxicity in HAECs. These findings add a novel aspect to the atheroprotective actions of LXR activators in cardiovascular disease.
Peter
Andreas
A
Department of Endocrinology, Diabetes, Vascular Medicine, Nephrology, and Clinical Chemistry, University of Tübingen, Otfried-Müller Strasse 10, Tübingen, Germany.
Weigert
Cora
C
Staiger
Harald
H
Rittig
Kilian
K
Cegan
Alexander
A
Lutz
Philipp
P
Machicao
Fausto
F
Häring
Hans-Ulrich
HU
Schleicher
Erwin
E
D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D050171:Dyslipidemias / Q000201:enzymology / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D004790:Enzyme Induction; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010168:Palmitates / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D004268:DNA-Binding Proteins; D005230:Fatty Acids, Nonesterified; D006845:Hydrocarbons, Fluorinated; D015850:Interleukin-6; D016209:Interleukin-8; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010168:Palmitates; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D013230:Stearoyl-CoA Desaturase; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C523776:SCD1 protein, human