MicroRNA‑802 increases hepatic oxidative stress and induces insulin resistance in high‑fat fed mice

Abstract

The expression of microRNA-802 (miR-802) is known to be associated with insulin resistance (IR); however, the mechanism remains unclear. The present study investigated how miR-802 contributes to the development of IR using C57BL/6J mice fed a high-fat diet (HFD) to establish a model of IR. Adeno-associated virus overexpressing miR-802 was administered to the mice via tail vein injection. The effects of miR-802 on reactive oxygen species (ROS), lipid peroxidation (LPO) and the activities of multiple ROS-related enzymes were investigated. Western blot analysis was used to estimate the protein levels of extracellular signal regulated kinase (ERK), p38mitogen-activated protein kinases (p38MAPK), c-Jun N-terminal kinase (JNK), insulin receptor substrate 1 (IRS-1) and protein kinase B (AKT1). The results demonstrated that the levels of ROS and LPO production were increased in the livers of the miR-802-treated group compared with the control group. The activities of the ROS-related enzymes were reduced. Furthermore, the expression of phosphorylated (phosphor)-p38MAPK and phosphor-JNK were upregulated in the miR-802 overexpression group, whereas there was no difference in the expression levels of phosphor-ERK. The expression levels of phosphor-AKT1 were reduced in the miR-802-treated group and these effects were reversed by miR-802 knockdown. In conclusion, the results demonstrate that miR-802 may cause IR by activating the JNK and p38MAPK pathways to increase hepatic oxidative stress.

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress

“…Furthermore, miR-802 induced the expression of phosphorylated p38MAPK and JNK, however, the levels of phospho-ERK remained unchanged. In conclusion, by means of miR-802, HFD may cause IR via activating the JNK and p38MAPK pathways and also suppressing antioxidative enzymes to induce hepatic OxS [ 214 ]. HG-promoted OxS along with IR in HepG2 cells was mediated by decreased levels of miR-233, thus preventing miR-233-dependent direct regulation of Keap1 and reducing levels of Nrf2, HO-1 and SOD1 [ 215 ].…”

Non-Coding RNAs as Potential Novel Biomarkers for Early Diagnosis of Hepatic Insulin Resistance

“…As is widely known, the damage occurring in target organs during diabetes is multicausal, so next to high glucose and fatty acids levels, the increased production of reactive oxygen species (ROS) also accounts for the damage. Yang et al [25] demonstrated a connection between miR-802, oxidative stress, and hepatic insulin resistance. In their study, they showed that in HFD mice, miR-802 upregulation was associated not only with higher blood glucose and serum insulin levels but also with a lowered activity of oxidative-stress related enzymes such as SOD (superoxide dismutase), CAT (catalase), and GSH-Px (glutathione peroxidase).…”

Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs

“…In one example, the strong induction of lnc7169 by TCPOBOP may contribute to the hepatoprotective effects of CAR activation on high fat diet-induced non-alcoholic fatty liver disease [88,89] by increasing expression of the divergently transcribed Gdf15, a stress response cytokine that is induced by inflammation, acute injury and oxidative stress [58]. In contrast, the very strong induction by TCPOBOP of lnc13509 may stimulate the divergent transcription of miR802, whose expression is elevated in type-II diabetes [64] and in livers of high fat diet-fed mice, where it impairs glucose metabolism and increases oxidative stress [65][66][67]. Alternatively, lnc13509 could serve as hepatoprotective miRNA sponge [90] that depletes miR802, which may be investigated using a variety of experimental and computational approaches [91,92], including innovative knockout technologies [30] that may uncover its biological functions and gene targets in the liver.…”

“…We hypothesize that the induction of lnc13509 impacts various biological and pathological responses regulated by miR802. Elevated expression of miR802 is seen in type-II diabetes [64] and in livers of high fat diet-fed mice, where it impairs glucose metabolism by silencing the transcription factor HNF1b and by increasing oxidative stress [65][66][67]. Further, miR802 shows female-biased expression in mouse liver; it preferentially represses many male-biased mRNAs and increases levels of female-biased mRNAs in female liver [68] and has been associated with regulation of glucose and lipid metabolism [67].…”