Background & aims

The paradox of selective hepatic insulin resistance, wherein the insulin-resistant liver fails to suppress glucose production but continues to produce lipids, has been central to the pathophysiology of hepatosteatosis and hyperglycemia. Our study was designed to investigate the mechanism(s) by which microRNA-206 alleviates the pathogenesis of hepatosteatosis and hyperglycemia.

Methods

Dietary obese mice induced by a high fat diet were used to study the role of microRNA-206 in the pathogenesis of hepatosteatosis and hyperglycemia. A mini-circle vector was used to deliver microRNA-206 into the livers of mice.

Results

Lipid accumulation impaired biogenesis of microRNA-206 in fatty livers of dietary obese mice and human hepatocytes (p<0.01). Delivery of microRNA-206 into the livers of dietary obese mice resulted in the strong therapeutic effects on hepatosteatosis and hyperglycemia. Mechanistically, miR-206 interacted with the 3' untranslated region of PTPN1 (protein tyrosine phosphatase, non-receptor type 1) and induced its degradation. By inhibiting PTPN1 expression, microRNA-206 facilitated insulin signaling by promoting phosphorylation of INSR (insulin receptor) and impaired hepatic lipogenesis by inhibiting Srebp1c transcription. By simultaneously modulating lipogenesis and insulin signaling, microRNA-206 reduced lipid (p=0.006) and glucose (p=0.018) production in human hepatocytes and livers of dietary obese mice (p<0.001 and p<0.01 respectively). Re-introduction of Ptpn1 into livers offset the inhibitory effects of microRNA-206, indicating that PTPN1 mediates the inhibitory effects of microRNA-206 on both hepatosteatosis and hyperglycemia.

Conclusions

MicroRNA-206 is a potent inhibitor of lipid and glucose production by simultaneously facilitating insulin signaling and impairing hepatic lipogenesis. Our findings potentially provide a novel therapeutic agent for both hepatosteatosis and hyperglycemia.

Lay summary

The epidemic of obesity is causing a sharp rise in the incidence of insulin resistance and its major complications, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). However, there are no effective treatments because the mechanisms underlying both disorders are not well described. We identified microRNA-206 as a novel and effective inhibitor for both glucose and lipid production in liver and potentially provide a unique therapeutic drug for both hepatosteatosis and hyperglycemia.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here, we report that microRNA-206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell-cycle progression and the cMet signaling pathway. MicroRNA-206 was underexpressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto-oncogene), cyclin D1 (CCND1), and cyclin-dependent kinase 6 (CDK6) as functional targets of microRNA-206. By inhibiting expression of cMET, CCND1, and CDK6, microRNA-206 delayed cell-cycle progression, induced apoptosis, and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA-206 completely prevented HCC development in both cMyc and V-Akt murine thymoma viral oncogene homolog 1/neuroblastoma RAS viral oncogene homolog (AKT/Ras) HCC mice, whereas 100% of control mice died from lethal tumor burdens. Conversely, reintroduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA-206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA-206 on the development of HCC. MicroRNA-206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice.

Conclusion

In summary, this study defines a potentially critical role of microRNA-206 in preventing the growth of HCC and suggests its use as a potential therapeutic strategy for this malignancy. (Hepatology 2017;66:1952-1967).