title: A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver.
abstract: Identification of microRNAs (miRNAs) that regulate lipid metabolism is important to advance the understanding and treatment of some of the most common human diseases. In the liver, a few key miRNAs have been reported that regulate lipid metabolism, but since many genes contribute to hepatic lipid metabolism, we hypothesized that other such miRNAs exist. To identify genes repressed by miRNAs in mature hepatocytes in vivo, we injected adult mice carrying floxed Dicer1 alleles with an adenoassociated viral vector expressing Cre recombinase specifically in hepatocytes. By inactivating Dicer in adult quiescent hepatocytes we avoided the hepatocyte injury and regeneration observed in previous mouse models of global miRNA deficiency in hepatocytes. Next, we combined gene and miRNA expression profiling to identify candidate gene/miRNA interactions involved in hepatic lipid metabolism and validated their function in vivo using antisense oligonucleotides. A candidate gene that emerged from our screen was lipoprotein lipase (Lpl), which encodes an enzyme that facilitates cellular uptake of lipids from the circulation. Unlike in energy-dependent cells like myocytes, LPL is normally repressed in adult hepatocytes. We identified miR-29a as the miRNA responsible for repressing LPL in hepatocytes, and found that decreasing hepatic miR-29a levels causes lipids to accumulate in mouse livers.
  
  
  CONCLUSIONS
  Our screen suggests several new miRNAs are regulators of hepatic lipid metabolism. We show that one of these, miR-29a, contributes to physiological lipid distribution away from the liver and protects hepatocytes from steatosis. Our results, together with miR-29a's known antifibrotic effect, suggest miR-29a is a therapeutic target in fatty liver disease.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA; Department of Pathology, University of California San Francisco, San Francisco, CA; Liver Center, University of California San Francisco, San Francisco, CA.
authors.forename: Aras N
authors.initials: AN
authors.lastname: Mattis
authors.forename: Guisheng
authors.initials: G
authors.lastname: Song
authors.forename: Kelly
authors.initials: K
authors.lastname: Hitchner
authors.forename: Roy Y
authors.initials: RY
authors.lastname: Kim
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Lee
authors.forename: Amar D
authors.initials: AD
authors.lastname: Sharma
authors.forename: Yann
authors.initials: Y
authors.lastname: Malato
authors.forename: Michael T
authors.initials: MT
authors.lastname: McManus
authors.forename: Christine C
authors.initials: CC
authors.lastname: Esau
authors.forename: Erich
authors.initials: E
authors.lastname: Koller
authors.forename: Suneil
authors.initials: S
authors.lastname: Koliwad
authors.forename: Lee P
authors.initials: LP
authors.lastname: Lim
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Maher
authors.forename: Robert L
authors.initials: RL
authors.lastname: Raffai
authors.forename: Holger
authors.initials: H
authors.lastname: Willenbring
mesh_terms: D000818:Animals; D004794:Enzyme Repression; D005234:Fatty Liver / Q000209:etiology; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*
chemical_list: C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D008071:Lipoprotein Lipase