miR-145 improves metabolic inflammatory disease through multiple pathways

J Mol Cell Biol. 2020 Feb 20;12(2):152-162. doi: 10.1093/jmcb/mjz015.

Abstract

Chronic inflammation plays a pivotal role in insulin resistance and type 2 diabetes, yet the mechanisms are not completely understood. Here, we demonstrated that serum LPS levels were significantly higher in newly diagnosed diabetic patients than in normal control. miR-145 level in peripheral blood mononuclear cells decreased in type 2 diabetics. LPS repressed the transcription of miR-143/145 cluster and decreased miR-145 levels. Attenuation of miR-145 activity by anti-miR-145 triggered liver inflammation and increased serum chemokines in C57BL/6 J mice. Conversely, lentivirus-mediated miR-145 overexpression inhibited macrophage infiltration, reduced body weight, and improved glucose metabolism in db/db mice. And miR-145 overexpression markedly reduced plaque size in the aorta in ApoE-/- mice. Both OPG and KLF5 were targets of miR-145. miR-145 repressed cell proliferation and induced apoptosis partially by targeting OPG and KLF5. miR-145 also suppressed NF-κB activation by targeting OPG and KLF5. Our findings provide an association of the environment with the progress of metabolic disorders. Increasing miR-145 may be a new potential therapeutic strategy in preventing and treating metabolic diseases such as type 2 diabetes and atherosclerosis.

Keywords: Kruppel-like factor 5; NF-κB; monocyte; osteoprotegerin; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Atherosclerosis / drug therapy*
  • Diabetes Mellitus, Type 2 / blood*
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Genetic Vectors / pharmacology
  • Genetic Vectors / therapeutic use
  • Glucose / pharmacology
  • Glucose Intolerance / blood*
  • HEK293 Cells
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • MicroRNAs / pharmacology
  • MicroRNAs / therapeutic use*
  • Oligonucleotides, Antisense / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • THP-1 Cells
  • Transfection

Substances

  • MIRN145 microRNA, human
  • MIRN145a microRNA, mouse
  • MicroRNAs
  • Oligonucleotides, Antisense
  • Glucose