Abstract 15888: Elevations in the Cholesterol Metabolite 27-Hydroxycholesterol Cause Insulin Resistance in Mice
Type 2 diabetes is frequently a comorbidity with hypercholesterolemia. How hypercholesterolemia contributes to insulin resistance is poorly understood. We previously discovered that the cholesterol metabolite 27-hydroxycholesterol (27HC), which is synthesized by CYP27A1 and metabolized by CYP7B1, is an endogenous selective estrogen receptor (ER) modulator (SERM). The present study was designed to determine how 27HC impacts glucose homeostasis in mice. In chow-fed CYP7B1-/- males with elevated 27HC and normal total cholesterol, fasting glucose was elevated and glucose tolerance tests (GTT) were abnormal. In hyperinsulinemic-euglycemic clamps the glucose infusion rate (GIR) was decreased by 50% in CYP7B1-/- versus CYP7B1+/+, indicating marked insulin resistance. This was associated with both attenuated glucose disposal and hepatic insulin resistance. In males on high fat/high cholesterol western diet for 12 weeks, the abnormalies in GTT, clamp GIR and hepatic insulin sensitivity were more exaggerated in CYP7B1-/- versus CYP7B1+/+. Confirming that the glucose intolerance in CYP7B1-/- is due to elevated 27HC, wild-type males administered 27HC for 12 weeks displayed fasting hyperglycemia and abnormal GTTs. To determine if the effects of 27HC involve its activity as a SERM, the impact of estradiol (E2) on glucose homeostasis was evaluated in ovariectomized female CYP7B1+/+ versus CYP7B1-/- mice on western diet for 12 weeks. GTT were more abnormal in vehicle-treated CYP7B1-/- versus CYP7B1+/+ females, and whereas GTT improved in response to E2 in CYP7B1+/+, E2 had no impact on GTT in CYP7B1-/-. In addition, fasting insulin was higher in vehicle-treated CYP7B1-/- versus CYP7B1+/+, and although normalized by E2 in CYP7B1+/+, fasting insulin remained elevated despite E2 in CYP7B1-/-. Thus, elevations in the cholesterol metabolite 27HC cause insulin resistance in mice, and this entails both attenuated glucose disposal and hepatic insulin resistance. These effects are at least partially related to 27HC action as a SERM. The targeting of 27HC synthesis or metabolism or mechanism of action may afford novel means to combat type 2 diabetes in the setting of hypercholesterolemia or other conditions in which 27HC is elevated, such as with advanced age.
- © 2013 by American Heart Association, Inc.