SCD1 is essential for the prevention of hypercholesterolemia and hepatic dysfunction elicited by a very low‐fat, high carbohydrate diet

Although both dietary and endogenously synthesized monounsaturated fatty acids (MUFA) contribute to the whole body pool, de novo synthesis is the predominant source during very low‐fat, high‐carbohydrate (VLF‐HC) feeding. Stearoyl‐CoA desaturase 1‐deficient (SCD1−/ −) mice have impaired MUFA synthesis. When maintained on a VLF‐HC diet, SCD1−/ − mice develop severe hypercholesterolemia characterized by an increase in apolipoprotein B‐containing lipoproteins and the appearance of lipoprotein‐X. Additionally, high‐density lipoprotein cholesterol is dramatically reduced in VLF‐HC SCD1−/ − mice. The fractional clearance rate of [ 125 I]‐low‐density lipoprotein (LDL) was decreased in VLF‐HC SCD1−/ − mice relative to VLF‐HC SCD1+/+ mice, demonstrating that decreased LDL clearance contributes to the hypercholesterolemic phenotype. The concomitant presence of elevated plasma bile acids and bilirubin in the VLF‐HC SCD1−/ − mouse are indicative of hepatic dysfunction and consistent with the clinical presentation of cholestasis. Supplementation of the VLF‐HC diet with unsaturated fat (canola oil), but not saturated fat (coconut oil), prevents these plasma phenotypes. However, oleate was not as effective as canola oil in reducing LDL‐cholesterol, signifying an additional role for dietary polyunsaturated fatty acids in the development of this phenotype. These results indicate that lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis and to prevent hypercholesterolemia and hepatic dysfunction. This work was supported by National Institutes of Health grants DK07665, DK58037, DK66369, and HL56593.