Stearoyl-CoA desaturase deficiency, hypercholesterolaemia, cholestasis and diabetes.

Previous studies have shown that mice deficient in Scd1 have a dramatically reduced level of liver triglyceride and an improvement in insulin sensitivity. The mice are lean and partially protected from obesity induced by leptin deficiency or high fat diets. These results predicted that Scd1(-/-) mice would be protected from the increased serum triglyceride levels that result from a lipogenic diet and might also might protect a diabetes-susceptible obese mouse strain from diabetes. We studied Scd1(-/-) mice on a very low-fat high-carbohydrate lipogenic diet. The animals were almost entirely devoid of high density lipoprotein (HDL). Nonetheless, they were hypercholesterolaemic due to a large increase in low density lipoprotein (LDL). They had a high level of serum bilirubin and bile acids, and the appearance of lipoprotein-X, indicative of cholestasis. These changes were reversible with oil containing both mono- and polyunsaturated fat, but not entirely reversible with just triolein, suggesting that Scd1 deficiency increased the requirement for polyunsaturated fat. We performed hyperinsulinemic-euglycemic clamp experiments and found that the Scd1(-/-) mice on a normal chow diet had dramatically improved insulin sensitivity. But, surprisingly, leptin(ob/ob) Scd1(-/-) mice had worse diabetes than leptin(ob/ob) Scd1(wt/wt) mice. Thus, despite its effects on insulin sensitivity, Scdl deficiency worsens diabetes in leptin-deficient obese mice.