Long noncoding RNA MALAT1 regulates generation of reactive oxygen species and the insulin responses in male mice. | Academic Article individual record
abstract

The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA and its overexpression is associated with the development of many types of malignancy. MALAT1 null mice show no overt phenotype. However, in transcriptome analysis of MALAT1 null mice we found significant upregulation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulated antioxidant genes including Nqo1 and Cat with significant reduction in reactive oxygen species (ROS) and greatly reduced ROS-generated protein carbonylation in hepatocyte and islets. We performed lncRNA pulldown assay using biotinylated antisense oligonucleotides against MALAT1 and found MALAT1 interacted with Nrf2, suggesting Nrf2 is transcriptionally regulated by MALAT1. Exposure to excessive ROS has been shown to cause insulin resistance through activation of c-Jun N-terminal kinase (JNK) which leads to inhibition of insulin receptor substrate 1 (IRS-1) and insulin-induced phosphorylation of serine/threonine kinase Akt. We found MALAT1 ablation suppressed JNK activity with concomitant insulin-induced activation of IRS-1 and phosphorylation of Akt suggesting MALAT1 regulated insulin responses. MALAT1 null mice exhibited sensitized insulin-signaling response to fast-refeeding and glucose/insulin challenges and significantly increased insulin secretion in response to glucose challenge in isolated MALAT1 null islets, suggesting an increased insulin sensitivity. In summary, we demonstrate that MALAT1 plays an important role in regulating insulin sensitivity and has the potential as a therapeutic target for the treatment of diabetes as well as other diseases caused by excessive exposure to ROS.

publication outlet

Biochem Pharmacol

author list (cited authors)
Chen, J., Ke, S., Zhong, L., Wu, J., Tseng, A., Morpurgo, B., ... Tian, Y.
publication date
2018
publisher
Elsevier BV Publisher
keywords
  • Protein Carbonylation
  • Mice
  • Long Noncoding Rna
  • Reactive Oxygen Species
  • Insulin
  • Insulin Resistance
  • Male
  • Oxidative Stress
  • Gene Expression Regulation
  • Signal Transduction
  • T2dm
  • Mice, Knockout
  • Rna, Long Noncoding
  • Animals
altmetric score

0.25

citation count

37

PubMed ID
29577871
identifier
346580SE
Digital Object Identifier (DOI)
start page
94
end page
103
volume
152