miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.
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.
Esau
Christine
C
Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008, USA. cesau@isisph.com
Davis
Scott
S
Murray
Susan F
SF
Yu
Xing Xian
XX
Pandey
Sanjay K
SK
Pear
Michael
M
Watts
Lynnetta
L
Booten
Sheri L
SL
Graham
Mark
M
McKay
Robert
R
Subramaniam
Amuthakannan
A
Propp
Stephanie
S
Lollo
Bridget A
BA
Freier
Susan
S
Bennett
C Frank
CF
Bhanot
Sanjay
S
Monia
Brett P
BP
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
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