title: miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.
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.
authors.affiliation: Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008, USA. cesau@isisph.com
authors.forename: Christine
authors.initials: C
authors.lastname: Esau
authors.forename: Scott
authors.initials: S
authors.lastname: Davis
authors.forename: Susan F
authors.initials: SF
authors.lastname: Murray
authors.forename: Xing Xian
authors.initials: XX
authors.lastname: Yu
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Pandey
authors.forename: Michael
authors.initials: M
authors.lastname: Pear
authors.forename: Lynnetta
authors.initials: L
authors.lastname: Watts
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Booten
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.forename: Robert
authors.initials: R
authors.lastname: McKay
authors.forename: Amuthakannan
authors.initials: A
authors.lastname: Subramaniam
authors.forename: Stephanie
authors.initials: S
authors.lastname: Propp
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Lollo
authors.forename: Susan
authors.initials: S
authors.lastname: Freier
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D001774:Blood Chemical Analysis; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D005227:Fatty Acids; D035683:MicroRNAs; D009097:Multienzyme Complexes; D016376:Oligonucleotides, Antisense; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases