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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) represents the most common liver disease in the whole world
The organization and sequences of the miR‐17‐92 family is highly conserved among vertebrates, and gene duplication and deletion events during evolution have resulted in two mammalian paralogs: the miR‐106b‐ 25 cluster and the miR‐106a‐363 cluster
The miRNAs encoded by miR‐17‐92 and its two paralogs can be grouped into four seed families
Summary
Nonalcoholic fatty liver disease (NAFLD) represents the most common liver disease in the whole world. Intrahepatocyte fat accumulation and systemic IR may influence with each other for leading to the progression of liver damage.[2] the genetic bases of NAFLD and nonalcoholic steatohepatitis (NASH) risk and the relationship with IR are far from clear. We aimed to identify the role of miR‐17 family‐mediated regulation of Pknox[1] in hepatic lipogenesis and IR, in order to seek new intervention targets for the prevention and treatment of progressive liver disease caused by T2DM and NAFLD complication
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