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

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 m...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2018-12, Vol.22 (12), p.6167-6175
Main Authors: Ye, Dan, Lou, Guohua, Zhang, Tianbao, Dong, Fengqin, Liu, Yanning
Format: Article
Language:English
Subjects:
3' Untranslated regions
Animals
Conserved sequence
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Experimental - pathology
Diabetes Mellitus, Type 2 - complications
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - pathology
Ectopic expression
Fatty acids
Fatty liver
Fatty Liver - complications
Fatty Liver - genetics
Fatty Liver - metabolism
Fatty Liver - pathology
Gene Expression Regulation
Hep G2 Cells
hepatocyte steatosis
Hepatocytes
High fat diet
Homeodomain Proteins - genetics
Humans
Insulin
Insulin - genetics
insulin resistance
Intracellular signalling
Kinases
Liver
Liver diseases
metabolic disease
MicroRNAs - genetics
miRNA
miR‐17 family
mRNA
Non-alcoholic Fatty Liver Disease - complications
Non-alcoholic Fatty Liver Disease - genetics
Non-alcoholic Fatty Liver Disease - pathology
Original
Phosphorylation
Pknox1
Proteins
Rats
Rodents
Signal transduction
Signal Transduction - genetics
Steatosis
Streptozocin
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Summary: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.
ISSN:1582-1838
1582-4934
DOI:10.1111/jcmm.13902