Statins Stimulate Hepatic Glucose Production via the miR-183/96/182 Cluster

Statins are the most common pharmacologic intervention in hypercholesterolemic patients, and their use is recognized as a key medical advance leading to a 50% decrease in deaths from heart attack or stroke over the past 30 years. The atheroprotective outcomes of statins are largely attributable to the accelerated hepatic clearance of low-density lipoprotein (LDL)-cholesterol from circulation, following the induction of the LDL receptor. However, multiple studies suggest that these drugs exert additional LDL-independent effects. The molecular mechanisms behind these so-called pleiotropic effects of statins, either beneficial or undesired, remain largely unknown. Here we determined the coding transcriptome, miRNome, and RISCome of livers from mice dosed with saline or atorvastatin to define a novel in vivo epitranscriptional regulatory pathway that links statins to hepatic gluconeogenesis, via the SREBP2-miR-183/96/182-TCF7L2 axis. Notably, multiple genome-wide association studies identified TCF7L2 (transcription factor 7 like 2) as a candidate gene for type 2 diabetes, independent of ethnicity. Conclusion: our data reveal an unexpected link between cholesterol and glucose metabolism, provides a mechanistic explanation to the elevated risk of diabetes recently observed in patients taking statins, and identifies the miR-183/96/182 cluster as an attractive pharmacological candidate to modulate non-canonical effects of statins.