The mir‐465 family is upregulated with age and attenuates growth hormone signaling in mouse liver

Abstract

We analyzed the small RNA transcriptome from 5‐month‐old, 24‐month‐old, and 36‐month‐old mouse liver and found 56 miRNAs that changed their expression profile with age. Among these is a cluster of 18 miRNAs that are upregulated between 50‐ and 1,000‐fold at 24 and 36 months of age. This cluster is located in a 60‐kb region of the X‐chromosome that is devoid of other coding sequences and is part of a lamin‐associated domain. Potential targets of the miRNAs in the cluster suggest they may regulate several pathways altered in aging, including the PI3K‐Akt pathway. Total transcriptome analyses indicate that expression of several potential genes in the PI3K‐Akt pathway that may be targeted by the mir‐465 family (mmu‐mir‐465a, mmu‐mir‐465b, and mmu‐mir‐465c) is downregulated with age. Transfection of the liver cell line AML12 with mir‐465 family members leads to a reduction of three of these potential targets at the mRNA level: a 40% reduction of the growth hormone receptor (GHR), and a 25% reduction in Kitl and PPP2R3C. Further investigation of the GHR 3′UTR revealed that the mir‐465 family directly targets the GHR mRNA. Cells transfected with mir‐465 showed a reduction of JAK2 and STAT5 phosphorylation upon growth hormone (GH) stimulation, resulting in a reduction in insulin‐like growth factor 1 (IGF‐1) and IGF‐1‐binding protein 3 expression. With age, GH signaling falls and there is a reduction in circulating IGF‐1. Our data suggest that an increase in expression of the mir‐465 family with age may contribute to the reduction in the GH signaling.

Cerebral Insulin Bolus Revokes the Changes in Hepatic Lipid Metabolism Induced by Chronic Central Leptin Infusion

“…Although synergistic actions of GH and insulin on STAT5 remain unclear, lower activation of STAT5 in a knockout of insulin receptor has been reported [ 46 ]. Moreover, transfection of a liver cell line with mir-465 mimics, which may affect genes of PI3K-Akt pathway, reduces STAT5 phosphorylation upon GH stimulation [ 47 ].…”

MicroRNA dysregulation influences growth hormone signaling

“…The mechanisms surrounding the natural reduction in GH and IGF-1 are not clearly understood. Recently, it was shown that the mir-465 family of miRNAs is upregulated with age in mouse liver and can directly influence GH signaling by targeting the GHR mRNA [4]. The mir-465 family consists of five genes located on the X-chromosome: one copy of mir-465a, and two copies each of mir-465b and mir-465c.…”

“…The mir-465 family is part of a cluster of 18 miRNAs that are normally tightly repressed in liver. However, all 18 miRNAs in this cluster are upregulated with age [4]. This cluster is located in a highly heterochromatic region of the X-chromosome that is rich in repetitive elements and devoid of other coding sequences, consistent with constitutive heterochromatin.…”

“…It is expressed in the hippocampus of the long-lived Ames Dwarf mouse, where it leads to a reduction in the IGF-1 receptor. Bioinformatic analyses predict that three additional miRNAs in the X-chromosomal cluster (mir-743a, mir-871, and mir-881) may target IGF-1 [4], signifying that the age-associated up-regulation of this cluster of miRNAs may contribute to the dysregulation of the somatotropic axis. GH signaling is highly intertwined with the PI3K-Alt signaling network, which regulates cell metabolism, proliferation, survival and growth.…”

“…Alterations in PI3K-Akt signaling has been implicated in the onset of many age-associated pathologies, including cancer, diabetes, and neurodegenerative conditions. Bioinformatic analyses predict 14 of the miRNAs in the X-chromosomal cluster have potential targets in 69 genes involved in PI3K-Akt signaling [4], suggesting that the 18 miRNAs may work together to contribute to the dysregulation of PI3K-Akt signaling with age, including GH signaling. Therefore, the age-associated upregulation of the X-chromosomal cluster of miRNAs may have impacts beyond GH signaling by influencing multiple pathways involved in cell growth and metabolism.…”