Roles of altered hepatic miRNA signatures during diabetes

posted Jan 26, 2017, 1:10 AM by sourav ghosh   [ updated Jan 26, 2017, 3:08 AM ]
Malabika Datta
Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology, Delhi, India.

microRNAs (miRNAs) are a class of small (~ 22 nucleotides) non-coding RNA species that act by regulating the expression of their target genes by either mRNA degradation or translational repression. miRNAs are now widely believed to participate in several physiological cellular pathways and aberrant signatures are associated with the onset and progression of diverse diseases. We have been studying altered miRNA patterns in the livers of diabetic mice and the mechanisms by which these alterations precipitate into the observed metabolic deregulations during diabetes. Specifically, levels of miR-107 and miR-22-3p are abnormally increased in the livers of diabetic db/db mice. We show that miR-22-3p binds to the 3' UTR of TCF7 and downregulates it and this miR-mediated regulation of TCF7 increases the expression of enzymes of the gluconeogenic pathway in HepG2 cells. siRNA-mediated knockdown of TCF7 in HepG2 cells also cause similar upregulation of gluconeogenic genes. In vivo silencing of miR-22-3p by antagomiR administration lowered random as well as fasting glucose levels in diabetic mice. miR-22-3p antagonism improved glucose tolerance and insulin sensitivity. Importantly, the hepatic Tcf7 levels were restored along with reduced hepatic glucose output which was also reflected by decreased expression of gluconeogenic genes. Our results support a critical role for miR-22-3p and its target, Tcf7 in the pathogenesis of diabetes by up-regulating gluconeogenesis. miR-107, on the other hand, regulates fatty acid synthase (FASN) and reduces its protein levels. Overexpression of miR-107 led to significant accumulation of malonyl CoA, accompanied by ER stress induction. This was followed by increased triglyceride formation and lipid accumulation in the presence of miR-107. These indicate that miR-107 inhibits FASN levels and this interaction promotes ER stress induction and malonyl CoA and lipid accumulation in HepG2 cells and primary hepatocytes.miR-107 also significantly inhibited the mitochondrial β-oxidation enzyme, HADHA, in HepG2 cells and this was rescued by ER stress inhibition. Over-expression of miR-107 in mice increased random blood glucose levels, impaired oral glucose tolerance and promoted hepatic lipid accumulation. These suggest that altered miRNA levels regulate metabolic processes that are reflected in terms of hyperglycemia and increase hepatic lipid accumulation during diabetes.