Dataset Information

CircRNA-PI4KB Induces Hepatic Lipid Deposition in Non-Alcoholic Fatty Liver Disease by Transporting miRNA-122 to Extra-Hepatocytes.

ABSTRACT: Ectopic fat deposition in the liver, known as non-alcoholic fatty liver disease (NAFLD), affects up to 30% of the worldwide population. miRNA-122, the most abundant liver-specific miRNA, protects hepatic steatosis and inhibits cholesterol and fatty acid synthesis in NAFLD. Previously, we have shown that compared with its expression in healthy controls, miRNA-122 decreased in the liver tissue but gradually increased in the serum of patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, suggesting that miRNA-122 could have been transported to the serum. Here, we aimed to confirm and unravel the mechanism of transportation of miRNA-122 to extra-hepatocytes. Our findings showed a decrease in the intra-hepatocyte miRNA-122 and an increase in the extra-hepatocyte (medium level) miRNA-122, suggesting the miRNA-122 "escaped" from the intra-hepatocyte due to an increased extra-hepatocyte excretion. Using bioinformatics tools, we showed that miRNA-122 binds to circPI4KB, which was further validated by an RNA pull-down and luciferase reporter assay. The levels of circPI4KB in intra- and extra-hepatocytes corresponded to that of miRNA-122, and the overexpression of circPI4KB increased the miRNA-122 in extra-hepatocytes, consequently accomplishing a decreased protective role of miRNA-122 in inhibiting the lipid deposition. The present study provides a new explanation for the pathogenesis of the hepatic lipid deposition in NAFLD.

SUBMITTER: Liu CH

PROVIDER: S-EPMC9863671 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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CircRNA-PI4KB Induces Hepatic Lipid Deposition in Non-Alcoholic Fatty Liver Disease by Transporting miRNA-122 to Extra-Hepatocytes.

Liu Chang-Hai CH Jiang Wei W Zeng Qingmin Q Wu Dongbo D Li Hong H Zhou Lingyun L Bai Lang L Tang Hong H

International journal of molecular sciences 20230109 2

Ectopic fat deposition in the liver, known as non-alcoholic fatty liver disease (NAFLD), affects up to 30% of the worldwide population. miRNA-122, the most abundant liver-specific miRNA, protects hepatic steatosis and inhibits cholesterol and fatty acid synthesis in NAFLD. Previously, we have shown that compared with its expression in healthy controls, miRNA-122 decreased in the liver tissue but gradually increased in the serum of patients with non-alcoholic fatty liver disease and non-alcoholic ...[more]

PMID: 36674813

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Project description:ObjectiveIt is well established that the liver-specific miR-122, a bona fide tumor suppressor, plays a critical role in lipid homeostasis. However, its role, if any, in amino acid metabolism has not been explored. Since glutamine (Gln) is a critical energy and anaplerotic source for mammalian cells, we assessed Gln metabolism in control wild type (WT) mice and miR-122 knockout (KO) mice by stable isotope resolved metabolomics (SIRM) studies.MethodsSix-to eight-week-old WT and KO mice and 12- to 15-month-old liver tumor-bearing mice were injected with [U-13C5,15N2]-L-Gln, and polar metabolites from the liver tissues were analyzed by nuclear magnetic resonance (NMR) imaging and ion chromatography-mass spectrometry (IC-MS). Gln-metabolism was also assessed in a Gln-dependent hepatocellular carcinoma (HCC) cell line (EC4). Expressions of glutaminases (Gls and Gls2) were analyzed in mouse livers and human primary HCC samples.ResultsThe results showed that loss of miR-122 promoted glutaminolysis but suppressed gluconeogenesis in mouse livers as evident from the buildup of 13C- and/or 15N-Glu and decrease in glucose-6-phosphate (G6P) levels, respectively, in KO livers. Enhanced glutaminolysis is consistent with the upregulation of expressions of Gls (kidney-type glutaminase) and Slc1a5, a neutral amino acid transporter in KO livers. Both Gls and Slc1a5 were confirmed as direct miR-122 targets by the respective 3'-UTR-driven luciferase assays. Importantly, expressions of Gls and Slc1a5 as well as glutaminase activity were suppressed in a Gln-dependent HCC (EC4) cell line transfected with miR-122 mimic that resulted in decreased 13C-Gln, 13C-á-ketoglutarate, 13C-isocitrate, and 13C-citrate levels. In contrast, 13C-phosphoenolpyruvate and 13C-G6P levels were elevated in cells expressing ectopic miR-122, suggesting enhanced gluconeogenesis. Finally, The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) database analysis showed that expression of GLS is negatively correlated with miR-122 in primary human HCCs, and the upregulation of GLS RNA is associated with higher tumor grade. More importantly, patients with higher expressions of GLS or SLC1A5 in tumors exhibited poor survival compared with those expressing lower levels of these proteins.ConclusionsCollectively, these results show that miR-122 modulates Gln metabolism both in vitro and in vivo, implicating the therapeutic potential of miR-122 in HCCs that exhibit relatively high GLS levels.

Project description:BackgroundHepatic fibrosis is a widespread disease worldwide. Millions of people lose their lives due to hepatic fibrosis every year. The main causes of hepatic fibrosis include viral infection, alcoholism, and obesity. Many studies have been conducted on the single factors that cause hepatic fibrosis; however, no studies have examined whether hepatic fibrosis caused by multiple factors has concomitant expression molecules and signaling pathways. In this study, we sought to analyze the common differentially expressed messenger ribonucleic acids (mRNAs) of hepatic fibrosis caused by different factors, including hepatitis B virus (HBV) hepatic fibrosis, alcoholic hepatic fibrosis, and non-alcoholic hepatic fibrosis, and identify potential preventive and therapeutic targets.MethodsThe GSE171294, GSE142530, and GSE126848 datasets from the Gene Expression Omnibus (GEO) public database were used in this study. A |log fold change| >0.5 and a P value <0.05 were defined as differentially expressed mRNAs via R software screening. To further screen the target mRNAs, the differential mRNAs were subjected to a functional enrichment analysis based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Finally, the relationships between differentially expressed mRNA-encoded proteins were analyzed by a protein-protein interaction (PPI) analysis.ResultsA total of 54 differentially expressed mRNAs were identified. The KEGG analysis showed that the functions of different mRNAs mainly focused on Gonadotropin Releasing Hormone (GnRH) secretion, bile secretion and insulin secretion. The GO enrichment analysis showed that the differential mRNAs were mainly present in the cytoplasmic membrane region and exerted biological functions, such as activating channels and binding proteins by regulating biological processes (BPs), such as cells, cytoskeleton and heparin. The PPI network analysis revealed 16 nodes with 12 pairs of interactions. The 16 critical nodes included BCL6, CD4, CD24, IL32, CALD1, TRAF3, SOX9, KANSL3, MRGBP, PKD2, PKHD1, SYT1, ANXA4, KCNMA1, KCNN2, and CACNA1H.ConclusionsKCNN2, CD4, CD24, BCL6, KCNMA1, and other molecules obtained by the bioinformatics analysis of the RNA-sequencing data can be used as new research targets for hepatic fibrosis induced by different causes. Our findings could provide novel ideas for the treatment of hepatic fibrosis.

Dataset Information

CircRNA-PI4KB Induces Hepatic Lipid Deposition in Non-Alcoholic Fatty Liver Disease by Transporting miRNA-122 to Extra-Hepatocytes.

Publications

CircRNA-PI4KB Induces Hepatic Lipid Deposition in Non-Alcoholic Fatty Liver Disease by Transporting miRNA-122 to Extra-Hepatocytes.

Similar Datasets

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