Abstract 17961: Circulating MicroRNA-122 is Associated With Incident Metabolic Syndrome and Type-2-diabetes
Background: MicroRNA-122 (miR-122) is highly abundant in the liver and has been implicated in lipid and glucose homeostasis.
Methods: Circulating miR-122 levels were measured in the prospective population-based Bruneck Study (n=810) and the ASCOT trial (n=155 pre/post atorvastatin initiation). Using mass spectrometry, we measured 135 lipid subspecies and 93 plasma proteins in Bruneck participants. We also conducted mechanistic studies in pre-clinical models and cultured hepatocytes. We calculated risk ratios over up to 15 years follow-up for cardiometabolic diseases using pooled logistic and Cox regression, incorporating repeated miR-122 measurements.
Results: In the Bruneck Study, miR-122 was associated with an adverse metabolic profile, including insulin resistance, obesity, and prevalent metabolic syndrome and diabetes. MiR-122 positively correlated with lipid subspecies containing fatty acids that can be derived from hepatic de novo lipogenesis. In mice, miR-122 inhibition with antagomiR treatment down-regulated hepatic enzymes implicated in de novo lipogenesis and cholesterol synthesis. In the ASCOT trial, 10mg atorvastatin treatment led to a reduction in circulating miR-122 levels. A similar statin response was observed in mice and in primary hepatocytes. In the Bruneck Study, miR-122 was closely related to circulating levels of afamin, zinc-alpha-2-glycoprotein, and a wide range of apolipoproteins. The adjusted relative risk per SD higher log miR-122 was 1.60 (1.30-1.96; P<0.001) for metabolic syndrome, 1.37 (1.03-1.82; P=0.021) for type-2 diabetes, and 1.10 (0.90-1.33; P=0.330) for cardiovascular disease. Risk ratios were similar upon further adjustment, for women and men, and by clinical categories of adiposity.
Conclusion: This study provides strong evidence for an involvement of miR-122 in glucose and lipid metabolism. High miR-122 levels correlate with an adverse lipid profile and multiple metabolic abnormalities and are associated with a higher risk of new-onset metabolic syndrome and diabetes in the general community.
Author Disclosures: P. Willeit: None. X. Yin: None. D. Kaudewitz: None. P. Skroblin: None. A. Zampetaki: None. A.R. Moschen: None. C.M. Ramirez: None. L. Goedeke: None. N. Rotllan: None. E. Bonora: None. A.D. Hughes: None. S. Weger: None. C. Fernandez-Hernando: None. H. Tilg: None. J. Willeit: None. S. Kiechl: None. M. Mayr: None.
- © 2015 by American Heart Association, Inc.