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Abstract Nucleophosmin (NPM)/B23 is an important nucleolar phosphoprotein involved in the regulation of assorted cellular signaling pathways. In the present study, we revealed a critical role of NPM in liver insulin resistance. NPM is markedly upregulated in insulin-resistant liver tissues and palmitic acid (PA)-exposed HepG2 cells both at mRNA and protein levels. Ectopic expression of NPM in hepatocytes aggravated PA-induced insulin resistance, lipid droplet accumulation, glucose intake impairment as well as the expression of gluconeogenic genes. Coinciding with these results, interference of NPM using small interfering RNA (siRNA) oligos ameliorated PA-induced insulin resistance, as revealed by increased phosphorylation of AKT and GSK3β following insulin treatment. As predicted, PA-triggered alterations in glucose intake and the expression of gluconeogenic enzymes were attenuated following NPM depletion. Finally, we showed that NPM plays an indispensible role in PA-induced activation of NF-κB pathway. Both of NF-κB p65 phosphorylation and nuclear translocation were impeded by NPM interference in PA-treated HepG2 cells. Taken together, these findings explicitly demonstrate that NPM participates in the development of liver insulin resistance, suggesting that NPM may serve as a potential therapeutic target of type 2 diabetes. Highlights • NPM is upregulated in insulin resistant mice livers and hepatocytes • NPM aggravates PA-induced hepatic insulin resistance • Depletion of NPM ameliorates PA-triggered insulin resistance • NPM is required for NF-κB activation in PA-induced insulin resistance condition [ABSTRACT FROM AUTHOR]

Oxidative stress is an important pathogenesis of insulin resistance (IR) and Type 2 diabetes mellitus (T2DM). Studies have shown that knockdown of PTEN-induced putative kinase 1 (PINK1) causes oxidative stress and mitophagy. In db/db mice, PINK1 protein level is down-regulated. However, little is known regarding the mechanism by which PINK1 modulates IR in response to reactive oxygen species (ROS) induced stress. In our study, PINK1 expression decreased during palmitate (PA) induced IR in HepG2 cells and the hepatic tissues of high fat diet (HFD) fed mice. Additionally, free fatty acids (FFAs) could increase ROS and suppress insulin signaling pathway, which was indicated by reduced phosphorylation of protein kinase B (AKT) and glycogen synthase kinase 3β (GSK-3β). In addition, insulin induced glucose uptake decreased and the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key gluconeogenic enzymes, was up-regulated after PA treatment. Intriguingly, PINK1 overexpression could lead to opposite results. Moreover, PA induced hepatic IR through C-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways, which were rescued by PINK1 overexpression. In summary, our results demonstrate that PINK1 promoted hepatic IR via JNK and ERK pathway in PA treated HepG2 cells, implying a novel molecular target for the therapy of diabetes. [ABSTRACT FROM AUTHOR]

Studies have identified that PKM2 is related to the development of glucose intolerance and insulin resistance in rodents and humans. However, the underlying mechanism remains largely unknown. In the present study, we found that PKM2 expression was significantly elevated in insulin-resistant hepatic tissues and hepatocytes, implicating an association between PKM2 expression and hepatic insulin resistance (IR). In vitro study revealed that overexpression of PKM2 impaired the insulin signaling pathway by decreasing the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3β (GSK3β). Furthermore, PKM2 overexpression enhanced the effects of PA on the lipid accumulation, the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and hepatic glucose uptake. Intriguingly, PA-induced insulin resistance was suppressed following by the ablation of PKM2 in HepG2 cells. We also found that STAT3 was significantly activated by PKM2 overexpression. Moreover, we identified that PKM2 could interact directly with STAT3. Taken together, these studies demonstrate that PKM2 may promote hepatic IR via STAT3 pathway and would provide a new insight into dissecting the molecular pathogenesis of hepatic insulin resistance. [ABSTRACT FROM AUTHOR]