miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting |
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Authors: | Esau Christine Davis Scott Murray Susan F Yu Xing Xian Pandey Sanjay K Pear Michael Watts Lynnetta Booten Sheri L Graham Mark McKay Robert Subramaniam Amuthakannan Propp Stephanie Lollo Bridget A Freier Susan Bennett C Frank Bhanot Sanjay Monia Brett P |
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Institution: | Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008, USA. cesau@isisph.com |
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Abstract: | Current understanding of microRNA (miRNA) biology is limited, and antisense oligonucleotide (ASO) inhibition of miRNAs is a powerful technique for their functionalization. To uncover the role of the liver-specific miR-122 in the adult liver, we inhibited it in mice with a 2'-O-methoxyethyl phosphorothioate ASO. miR-122 inhibition in normal mice resulted in reduced plasma cholesterol levels, increased hepatic fatty-acid oxidation, and a decrease in hepatic fatty-acid and cholesterol synthesis rates. Activation of the central metabolic sensor AMPK was also increased. miR-122 inhibition in a diet-induced obesity mouse model resulted in decreased plasma cholesterol levels and a significant improvement in liver steatosis, accompanied by reductions in several lipogenic genes. These results implicate miR-122 as a key regulator of cholesterol and fatty-acid metabolism in the adult liver and suggest that miR-122 may be an attractive therapeutic target for metabolic disease. |
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Keywords: | HUMDISEASE CHEMBIO |
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