17 Stearoyl-CoA desaturase-1 (SCD1) is a key player in lipid metabolism. SCD1 catalyzes 18 the synthesis of monounsaturated fatty acids (MUFA). MUFA are then incorporated into 19 triacylglycerols and phospholipids. Previous studies have shown that Scd1 deficiency in 20 mice induces metabolic changes in the liver characterized by a decrease in de novo 21 lipogenesis and an increase in β-oxidation. Interestingly, Scd1 deficient mice show a 22 decrease in the expression and maturation of the

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... pal lipogenic transcription factor 23 SREBP-1. The mechanisms mediating this effect on de novo lipogenesis and β-oxidation 24 have not been fully elucidated. We evaluated the role of SCD1 on de novo lipogenesis 25 and β-oxidation in HepG2 cells. We also used Scd1 deficient mice and two strains of 26 transgenic mice that produce either oleate (GLS5) or palmitoleate (GLS3) in a liver-27 specific manner. We demonstrate that the expression of β-oxidation markers increases in 28 SCD1 deficient hepatocytes, and suggest that this is due to an increase in cellular 29 polyunsaturated fatty acid (PUFA) content. We also show that the changes in the level of 30 SREBP-1 expression, for both the precursor and the mature forms, are mainly due to the 31 lack of oleate in SCD1 deficient hepatocytes. Indeed, oleate treatment of cultured HepG2 32 cells or hepatic oleate production in chow-fed GLS5 mice can restore SREBP-1 33 expression and increases hepatic de novo lipogenesis. Finally, we show that oleate 34 specifically increases SREBP-1 nuclear accumulation, suggesting a central role for oleate 35 in SREBP-1 signaling activity. 36 37 Keywords 38 Stearoyl-CoA desaturase-1 (SCD1), Sterol receptor element binding protein-1 (SREBP-39 1), Fatty acid protein modification, De novo lipogenesis, β-oxidation 40