The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1

Stearoyl-CoA desaturase (SCD) is a microsomal enzyme required for the biosy nthesis of oleate and palmitoleate, which are the major monounsaturated fat ty acids of membrane phospholipids, triglycerides, and cholesterol esters. Two well characterized isoforms of SCD, SCD1 and SCD2, exist in the mouse. Most mouse tissues express SCD1 and 2 with the exception of the liver, whic h expresses mainly the SCD1 isoform. We found that asebia mice homozygous f or a natural mutation of the gene for SCD1 (SCD-/-) are deficient in hepati c cholesterol esters and triglycerides despite the presence of normal activ ities of acyl-CoA:cholesterol acyltransferase and glycerol phosphate acyltr ansferase, the enzymes responsible for cholesterol ester and triglyceride s ynthesis, respectively, in the liver of these mice. Feeding diets supplemen ted with triolein or tripalmitolein to the SCD-/- mice resulted in an incre ase in the levels of 16:1 and 18:1 in the liver but failed to restore the 1 8:1 and 16:1 levels of the cholesterol ester and triglycerides to the level s found in normal mice, The SCD-/- mouse had very low levels of triglycerid es in the VLDL and LDL lipoprotein fractions compared with the normal anima l. Transient transfection of an SCD1 expression vector into Chinese hamster ovary cells resulted in increased SCD activity and esterification of chole sterol to cholesterol esters. Taken together, our observations demonstrate that the oleoyl-CoA and palmitoleyl-CoA produced by SCD1 are necessary to s ynthesize enough cholesterol esters and triglycerides in the liver and sugg est that regulation of SCD1 activity plays an important role in mechanisms of cellular cholesterol homeostasis.