The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice

Abstract

Systemic iron homeostasis is mainly controlled by the liver through synthesis of the peptide hormone hepcidin (encoded by Hamp), the key regulator of duodenal iron absorption and macrophage iron release. Here we show that the liver-specific microRNA miR-122 is important for regulating Hamp mRNA expression and tissue iron levels. Efficient and specific depletion of miR-122 by injection of a locked-nucleic-acid-modified (LNA-modified) anti-miR into WT mice caused systemic iron deficiency, characterized by reduced plasma and liver iron levels, mildly impaired hematopoiesis, and increased extramedullary erythropoiesis in the spleen. Moreover, miR-122 inhibition increased the amount of mRNA transcribed by genes that control systemic iron levels, such as hemochromatosis (Hfe), hemojuvelin (Hjv), bone morphogenetic protein receptor type 1A (Bmpr1a), and Hamp. Importantly, miR-122 directly targeted the 3′ untranslated region of 2 mRNAs that encode activators of hepcidin expression, Hfe and Hjv. These data help to explain the increased Hamp mRNA levels and subsequent iron deficiency in mice with reduced miR-122 levels and establish a direct mechanistic link between miR-122 and the regulation of systemic iron metabolism.

Saturated Fatty Acids Induce Post-transcriptional Regulation of HAMP mRNA via AU-rich Element-binding Protein, Human Antigen R (HuR)

“…Unlike other iron-regulatory proteins, such as ferritin and transferrin receptor 1, which are regulated by RNA-binding proteins, IRP1 and IRP2, our knowledge on the post-transcriptional regulation of HAMP is very limited. An indirect role for microRNAs has been suggested in the regulation of mouse and human hepcidin genes via the targeting of transcriptional activators (17,18). In agreement, our findings in this study also indicated an indirect role for miR-214 in HAMP regulation by saturated fatty acids.…”

“…The results obtained from different databases commonly identified miR-214. Previous studies have also shown that miR-122 indirectly regulates HAMP gene expression by targeting 3Ј-UTR of other upstream iron-regulatory genes, such as Hfe and Hjv (17). We therefore included these two microRNAs in our investigations and determined the expression levels in PA-or solvent-treated HepG2 cells by qPCR as described under "Experimental Procedures."…”

“…An indirect role for miR-122 and miR-130a has been reported in the regulation of mouse and human hepcidin gene expression. Namely, miR-122 and miR-130a modulated HAMP expression by altering the mRNA stability of transcriptional activators, which are known to activate HAMP transcription (17,18). Other mechanisms besides microRNAs might be involved in direct targeting of HAMP 3Ј-UTR and post-transcriptional regulation of hepcidin expression.…”

MicroRNAs in Liver Disease: Bench to Bedside

“…40,44,45 Serum/plasma levels of miR-122 correlate with hepatic necro-inflammation, liver damage, cell death and increased aminotransferase levels in acute and chronic liver diseases. 44,[46][47][48][49] Interestingly, hepatic and circulating miR-122 levels do not correlate in NAFLD 14,39,[50][51][52][53][54][55] or viral hepatitis 41,47,49,56 although both have been statistically associated with various measures of disease severity in these studies. Together these studies show that miR-122 may play a role in most liver diseases.…”

“…[37][38][39] It is highly expressed in hepatocytes due to its liver specific transcriptional regulation by hepatic nuclear transcription factors 34,40 and is elevated in most hepatic diseases including hepatitis C virus (HCV) and hepatitis B virus (HBV) infections as well as alcohol and drug-induced liver injury, HCC and NAFLD. 13,14,[37][38][39][40][41][42][43][44][45] There are four miR-122 binding sites in the HCV genome 42 and miR-122 may promote viral replication by direct interaction with seed-sequencebinding to two target sites, S1 and S2, in the 5 0 -UTR of the HCV genome resulting in HCV-RNA genome stabilization and enhanced viral RNA abundance. 42,43 Dedifferentiation of hepatocytes during hepatocellular carcinogenesis is associated with the loss of miR-122.…”