BACKGROUNDPolyunsaturated fatty acids lower serum triglycerides by a mechanism that may involve the inhibition of stearoyl-CoA desaturase (SCD).OBJECTIVEWe sought to evaluate the effects of serum fatty acids on 1) the SCD index in a controlled clinical setting, and 2) SCD regulation in Hep G2 cells.METHODSThe SCD index was determined in 23 subjects randomly sequenced through 3 diets for 6 weeks in a crossover study. Diets were variably enriched with n-3 and n-6 polyunsaturated fatty acids; notably, monounsaturated fatty acids were held constant. Effects of linoleic acid (LA), α-linolenic acid (ALA), and eicosapentaenoic acid (EPA) on mRNA levels of SCD, fatty acid elongases 5 and 6 (Elovl5 and Elovl6), fatty acid synthase, carnitine palmitoyltransferase-1, and sterol response element binding protein-1c were investigated in Hep G2 cells after 24-hour incubations.RESULTSThe SCD indexes C18:1/18:0 and C16:1/C16:0 were significantly (P < .0001) correlated with serum TG with R(2) values of 0.71 and 0.58. The correlation was negatively associated with LA and positively associated with ALA. LA and EPA decreased SCD mRNA (EC(50) of 0.50 and 1.67μM), whereas ALA did not. Likewise, LA and EPA decreased sterol response element binding protein-1c mRNA (EC(50) of 0.78 and 1.78μM), but ALA did not. Similar results were observed for Elovl6. GW9662, a peroxisome proliferation activator receptor antagonist, did not obviate the effects of LA and EPA on SCD mRNA.CONCLUSIONSDiets enriched in LA, ALA, and by metabolic inference EPA, can regulate SCD activity at the level of transcription, a nutritional intervention that may be useful in the management of increased levels of serum triglycerides in cardiometabolic disorders.