MiR‐17 family‐mediated regulation of Pknox1 influences hepatic steatosis and insulin signaling

Abstract

The aberrant expression of Pknox1 is associated with hepatic glucose and lipid dysmetabolism status of type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism causing Pknox1 overexpression in this pathological status remains unclear. By using miRNA target prediction programs, we found that the 3′‐UTR of the Pknox1 mRNA sequence contains highly conserved target sites of miR‐17 family. In a rat model of streptozotocin and high‐fat diet‐induced T2DM and NAFLD complication, the increased hepatic expression of Pknox1 was consistent with decreased expressions of miR‐17 family, especially miR‐17 and miR‐20a. Furthermore, an inverse correlation was observed between Pknox1 and miR‐17 and miR‐20a in free fatty acids‐induced hepatocyte steatosis. Dual‐luciferase reporter assay further showed that Pknox1 was a valid target gene of miR‐17 family. The ectopic expression of miR‐17 or miR‐20a could markedly suppress Pknox1 expression in hepatocytes. MiR‐17 or miR‐20a overexpression also resulted in significantly enhanced insulin sensitivity and reduced hepatocyte steatosis in HepG2 and L02 cells, which were determined by altered phosphorylation on insulin receptor signaling pathway proteins and decreased intracellular triglyceride and lipid accumulation, respectively. These data implicate the upregulated hepatic expression of Pknox1 in T2DM complicated with NAFLD may be caused by the reduced expression of miR‐17 family, indicating that developing miRNA‐mediated regulation strategies on Pknox1 may provide new therapeutic options for metabolic disease.

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

“…In a rat model of streptozotocin and high-fat diet-induced T2D, miR-17 family, especially miR-17, was also downregulated in the hepatocytes. Moreover, miR-17 overexpression enhanced insulin sensitivity in HepG2 and LO2 cells, characterized by altered phosphorylation on Insr signaling pathway proteins 62 . However, there was a study reporting that miR-17 impaired glucose metabolism by repressing Glut4 in SkM of a high-fat diet STZ-induced rat model and palmitic acid-exposed L6 rat skeletal muscle cell line 63 .…”

Delayed Feeding Alters Transcriptional and Post-Transcriptional Regulation of Hepatic Metabolic Pathways in Peri-Hatch Broiler Chicks

“…Small interfering RNA-mediated reduction of SRF in a rat insulinoma cell line partially inhibited the ability of these cells to respond to glucose [31]. The transcriptional regulator PKNOX1 is higher in the livers of diabetic and non-alcoholic fatty liver disease patients [32]. It was found that PKNOX1 could be regulated by miR-17 family members, including miR-17 and miR-20a [32].…”

“…The transcriptional regulator PKNOX1 is higher in the livers of diabetic and non-alcoholic fatty liver disease patients [32]. It was found that PKNOX1 could be regulated by miR-17 family members, including miR-17 and miR-20a [32]. Overexpression of miR-17 and miR-20a in human hepatocytes increased the sensitivity of these cells to insulin and also decreased triglyceride and lipid accumulation [32].…”

“…It was found that PKNOX1 could be regulated by miR-17 family members, including miR-17 and miR-20a [32]. Overexpression of miR-17 and miR-20a in human hepatocytes increased the sensitivity of these cells to insulin and also decreased triglyceride and lipid accumulation [32]. As discussed above, HDAC2 is a histone deacetylase that regulates many different biological processes, including anti-oxidative mechanisms and gluconeogenesis [33].…”

MiR-20b Down-Regulates Intestinal Ferroportin Expression In Vitro and In Vivo

“…Moreover, the mature sequence and its ‘seed sequence’ of these four miRNAs were highly conserved among human, mouse, and pig based on identification of bioinformatics databases: miRbase [46], TargetScan [34], PicTar [43], PITA [36] and miRanda [44]. It is reported that miRNA-17 family plays a critical role in normal cardiac development, cardiovascular disease and polycystic kidney disease progression as well as affecting hepatic steatosis and insulin signaling [47,48,49,50,51,52]. Babu et al (2016) revealed that enhancing expression of miR-20a could decrease iron export and increase intracellular iron retention in lung cancer [32].…”