Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increases plasma high-density lipoprotein cholesterol induced by liver X receptor activation.
Stearoyl-coenzyme A desaturase (SCD) is the rate-limiting enzyme necessary for the biosynthesis of monounsaturated fatty acids. In this study, we investigated the regulation of mouse SCD1 by liver X receptor (LXR) and its role in plasma lipoprotein metabolism upon LXR activation. In vivo, the SCD1 gene remained induced upon LXR activation in the absence of sterol regulatory element-binding protein 1c (SREBP-1c), a known transcriptional regulator of SCD1. Serial deletion and point mutation analyses in reporter gene assays, as well as a gel mobility shift assay, identified an LXR response element in the mouse SCD1 promoter. In addition, SCD1 deficiency prevented the hypertriglyceridemic effect and reduced hepatic triglyceride accumulation associated with LXR activation despite induced hepatic expression of SREBP-1c protein and several SREBP1c and LXR target genes involved in lipoprotein metabolism. Unlike wild-type mice, SCD1-deficient mice failed to elevate the hepatic triglyceride monounsaturated acid (MUFA)/saturated fatty acid (SFA) ratio despite induction of the SCD2 gene. Together, these findings suggest that SCD1 plays a pivotal role in the regulation of hepatic and plasma triglyceride accumulation, possibly by modulating the MUFA-to-SFA ratio. In addition, SCD1 deficiency also increased plasma high-density lipoprotein cholesterol levels induced by LXR activation.
Chu
Kiki
K
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
Miyazaki
Makoto
M
Man
Weng Chi
WC
Ntambi
James M
JM
D000818:Animals; D001483:Base Sequence; D008076:Cholesterol, HDL / Q000097:blood*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D015228:Hypertriglyceridemia / Q000473:pathology*; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D000071518:Liver X Receptors; D051379:Mice; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D011485:Protein Binding / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000172:deficiency*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000172:deficiency; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C490333:Scd1 protein, mouse