miR-122, a Mammalian Liver-Specific microRNA, is Processed from hcr mRNA and MayDownregulate the High Affinity Cationic Amino Acid Transporter CAT-1

Abstract

These studies show that miR-122, a 22-nucleotide microRNA, is derived from a liver-specific noncoding polyadenylated RNA transcribed from the gene hcr. The exact sequence of miR-122 as well as the adjacent secondary structure within the hcr mRNA are conserved from mammalian species back to fish. Levels of miR-122 in the mouse liver increase to half maximal values around day 17 of embryogenesis, and reach near maximal levels of 50,000 copies per average cell before birth. Lewis et al. (2003) predicted the cationic amino acid transporter (CAT-1 or SLC7A1) as a miR-122 target. CAT-1 protein and its mRNA are expressed in all mammalian tissues but with lower levels in adult liver. Furthermore, during mouse liver development CAT-1 mRNA decreases in an almost inverse correlation with miR-122. Eight potential miR-122 target sites were predicted within the human CAT-1 mRNA, with six in the 3'-untranslated region. Using a reporter construct it was found that just three of the predicted sites, linked in a 400-nucleotide sequence from human CAT-1, acted with synergy and were sufficient to strongly inhibit protein synthesis and reduce mRNA levels. In summary, these studies followed the accumulation during development of miR-122 from its mRNA precursor, hcr, through to identification of what may be a specific mRNA target, CAT-1.

Selective stabilization of mammalian microRNAs by 3′ adenylation mediated by the cytoplasmic poly(A) polymerase GLD-2

“…miR-122 is a liver-specific miRNA that plays an important role in the regulation of hepatic function (Chang et al 2004;Krü tzfeldt et al 2005) and is highly expressed in hepatocytes and some hepatoma cells. miR-122 regulates cholesterol and fatty-acid metabolism, and depletion of miR-122 by an antisense oligo lowers the cholesterol level in plasma (Krü tzfeldt et al 2005).…”

The efficacy of miRNA122, a novel therapeutic target, for predicting the progression of hepatocellular carcinoma (HCC)

“…6 The best-known function of miRNA122 in the mammalian liver is to regulate lipid and cholesterol metabolism, and it is also involved in the replication of the hepatitis C virus. 7 Recently, miRNA122 has been reported to be downregulated in the tumor tissues of HCC patients.…”

MicroRNAs in Liver Disease: Bench to Bedside

“…123 MiR-122 is significantly down-regulated in humans and animal models of NAFLD patients. 12,14 The targeted deletion of miR-122a in mice results in NASH, fibrosis and HCC. 54 In miR profile analysis of high fat fed rat liver, 14 miRs were up-regulated and six were down-regulated, that might represent a distinctive molecular signature in the transition of steatosis to steatohepatitis.…”

“…8,9 MiRs are abundant in the liver and modulate a diverse spectrum of cellular processes associated with liver injury such as inflammation, apoptosis, and hepatocyte regeneration and deregulation of miR expression may be a key pathogenic factor in many liver diseases including viral hepatitis, hepatocellular carcinoma (HCC), metabolic and acute liver diseases; miR expression profiles are altered in many hepatic diseases compared to healthy subjects. [10][11][12][13][14] Many miRs are abundantly expressed in the liver; however miR-122 is liver specific, and is estimated to make up 70% of the total hepatic miR complement and is expressed at high levels (around 66,000 copies per cell). [10][11][12] Studies suggest that miRs are not only localized within the cell but are also present in circulation.…”

“…[10][11][12][13][14] Many miRs are abundantly expressed in the liver; however miR-122 is liver specific, and is estimated to make up 70% of the total hepatic miR complement and is expressed at high levels (around 66,000 copies per cell). [10][11][12] Studies suggest that miRs are not only localized within the cell but are also present in circulation. Extracellular circulating miRs can be found in lipid or lipoprotein complexes, apoptotic bodies, or actively secreted into microvesicles or exosomes, providing a mechanistic association between plasma miR level and specific organ dysfunction.…”