Premium
MicroRNAs in the Pathogenesis of Lipogenic Diet Induced Hyperlipidemia and Insulin Resistance
Author(s) -
Su Qiaozhu,
Sud Neetu,
Pan Kaichao
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.299.8
Subject(s) - microrna , biology , insulin resistance , messenger rna , downregulation and upregulation , three prime untranslated region , untranslated region , small rna , regulation of gene expression , gene , gene expression , microbiology and biotechnology , genetics , computational biology , insulin , endocrinology
Fructose is a highly lipogenic sugar which can alter energy metabolism and trigger metabolic disorders. MicroRNAs (miRNAs) are noncoding RNAs with a length of 19 to 25 nt and are involved in posttranscriptional gene regulation by binding to the 3′‐untranslated regions of their target mRNA and impacting diverse cellular processes, such as metabolic inflammation and energy metabolism. Regulation of miRNAs is tissue and cell type specific in which a single miRNA can target numerous mRNA sequences and each mRNA can be targeted by multiple miRNAs. This unique regulatory property enables miRNAs to simultaneously regulate several groups of mRNAs within a signaling pathway or network and generate powerful impact on diverse cellular processes. Thus, identification of miRNA expression profiles and their relevant target genes offers great potential to delineate the molecular pathogenesis of metabolic diseases. In this study, our objective was to comprehensively explore the regulatory roles of miRNAs in the onset of hyperlipidemia and insulin resistance induced by high fructose. Determination of the miRNA profile by illumina small RNA sequencing identified a set of miRNAs (forty six miRNAs) in mouse livers whose expression profiles were significantly altered by high‐fructose feeding. Among them, nineteen miRNAs were significantly upregulated whereas the other twenty six were downregulated compared to the control chow‐fed mice. Computational prediction and functional analysis further revealed that ten of these miRNAs, including miR‐19b‐3p, miR‐101a‐3p ‐3p, miR‐30a‐5p, miR‐223‐3p, miR‐378a‐3p, miR‐33‐5p, miR‐145a‐3p, miR‐128‐3p, miR‐125b‐5p and miR‐582‐3p, assembled as a regulatory network that collaboratively and repeatedly targets multiple key metabolic signaling molecules involved in inflammatory stress (e.g., PPARα and LXRα), lipid and lipoprotein metabolism (e.g., SREBP‐1/2 and apoB), and insulin signaling (e.g., IRS‐1 and FOXO1). Quantitative real‐time PCR analysis further confirmed that alterations of miRNAs were associated with the changes of the mRNA abundances of their target genes, indicating the pathogenic impact of the altered miRNAs on fructose induced metabolic disorders. Genetic depletion of miR‐378a protected mice from fructose induced insulin resistance whereas overexpression of miR‐378a resulted in inflammatory stress in hepatocytes. In conclusion, our study unveils a novel hepatic miRNA regulatory network that was altered by high‐fructose feeding. Manipulating the abundance of the key miRNAs in this network prevents the onset of hyperlipidemia and insulin resistance induced by high‐fructose diet. This novel finding provides mechanistic insights into the interaction between miRNAs and their target genes in the development of metabolic syndrome. It may further provide rationale for pharmaceutically targeting these miRNAs in the prevention and treatment of nutritional associated metabolic diseases. Support or Funding Information P20 GM104320‐01A