SCD1 is located in the liver and is responsible for the formation of oleyl-CoA. When oleyl-CoA is added to VLDL particles in the liver, the percentage of triacylglycerols present in the VLDL decreases.

Stearoyl-CoA Desaturase is an essential mixed-function oxidase. Stearoyl-CoA is converted to oleyl-CoA by the fatty acyl-CoA desaturase called stearoyl-CoA desaturase 1 in the liver (Lam, et al., 2007). The formation of a monounsaturated acyl-CoA from a saturated acyl-CoA in is one of the last steps in the synthesis of triglyceride droplets in VLDL particles (Figure 6). The VLDL particles, after formation in the liver, are released into the blood where they are stripped of their triglycerides in extra-hepatic tissues. LDL, low-density lipoprotein is the result of VLDL degradation as well as the release of bad cholesterol (Nelson and Cox , 2004).

Figure 6: Addition of oleyl-CoA to VLDL [Figure 3a, Lam, et al., 2007]

How the liver isozyme of stearoyl-CoA desaturase functions. Introduction of a double bond into a fatty acid is carried out through oxidation-reductions reactions (Figure 7). Introducing the double bond between the 9th and 10th carbon of stearoyl-CoA requires molecular oxygen and ferrochytochrome b5. SCD1 uses NAD as a cofactor in its enzymatic mechanism:

stearoyl-CoA + 2 ferrocytochrome b5 + O2 + 2 H+ = oleoyl-CoA + 2 ferricytochrome b5 + 2 H2O

Figure 7: Reactions catalyzed by SCD1 [King, 2003]

Measuring the change in oleyl-CoA levels. A hepatic desaturation index, the ratio of the concentration of oleyl-CoA to stearoyl-CoA, was used to measure the change in Stearoyl-CoA Desaturase 1 activity in vivo (Lam, et al., 2007) . By injecting the rat subjects with glucose, the hepatic desaturation index decreased significantly. As a result of brain glucose injections, not only did the hepatic expression of SCD1 decrease, but so too did the activity by approximately 70%.

The time frame for the injection of glucose followed by a decrease in the hepatic desaturation index is consistent with the metabolism rates observed in the rats. Within 60 minutes of infusion, the SCD1 activity was curtailed and the VLDL secretion as well as plasma triglyceride levels dropped.

Inhibiting Stearoyl-CoA Desaturase 1 activity in the liver. In order to ensure that limiting the activity of SCD1 was the reason for a decrease in VLDL secretion, a sequence-specific antisense oligodeoxynucleotide (ASO) was injected in the liver. The ASO specifically targeted SCD1 activity in the liver and reduced the levels of oleyl-CoA (Figure 10) production. These results are strong evidence that inhibition of SCD1 activity , which in turn decreases oleyl-CoA levels, is a means of decreasing VLDL secretion in humans.

Figure 8 : Stearoyl-CoA Structure

Figure 9: Oleyl-CoA Structure