Abstract 692: Therapeutic Inhibition of miR-33 Does Not Promote Obesity, Insulin Resistance or Hepatic Lipid Accumulation

Abstract

Inhibition of miR-33, a critical post-transcriptional regulator of cholesterol homeostasis, prevents atherosclerosis progression both dependently and independently of its effects on circulating HDL levels. However, recent studies suggest that genetic deletion or inhibition of miR-33 may adversely affect metrics of insulin resistance, lipid metabolism and hepatic steatosis. Given the therapeutic interest in miR-33 inhibitors for treating atherosclerosis, we sought to determine the effects of long-term pharmacological inhibition of miR33 in a mouse model of diet-induced obesity (DIO). Results: C57BL6/J mice were fed a high-fat diet in conjunction with anti-miR therapy (10mg/kg of control anti-miR or anti-miR33) for 20 weeks. There was significant but equivalent weight gain in all 3 groups. While anti-miR33 therapy increased total plasma cholesterol compared to control anti-miR treated mice (p≤0.01), there was no differences relative to PBS treated mice. Anti-miR33 treatment also resulted in a marked decrease in serum triglycerides relative to control anti-miR (29% decrease, p≤0.05) but once again not compared to PBS treated mice. Metrics of insulin resistance (GTT, ITT) were not altered in anti-miR33 treated mice relative to controls. Interestingly, indirect calorimetric measurements demonstrated that anti-miR33 treated mice had reduced respiratory exchange ratios (RER) compared to both control anti-miR and PBS treated mice (18% decrease, p≤0.05), suggesting an increase in fatty acid versus carbohydrate utilization in anti-miR33 treated mice. In addition, hepatic protein expression of known miR-33 target gene ABCA1 was de-repressed upon miR-33 inhibition, indicating that miR-33 was efficiently inhibited in this model. In contrast, putative miR-33 target gene SREBP-1 protein expression was not altered, nor were SREBP-1 downstream target genes FASN and ACC. Finally, anti-miR33 treated mice did not accumulate more lipids in their livers relative to control. In conclusion, we show in a DIO model that therapeutic silencing of miR-33 does not promote hepatic steatosis nor does it increase metrics of insulin resistance, suggesting that pharmacological inhibition of miR-33 may be a safe therapeutic for the treatment of atherosclerosis.