Circular RNA HIPK3 contributes to hyperglycemia and insulin homeostasis by sponging miR-192-5p and upregulating transcription factor forkhead box O1

Abstract

It has been shown that circular RNAs, a class of non-coding RNA molecules, play an important role in the regulation of glucose and lipid homeostasis. In the present study, we sought to investigate the function of circular RNA HIPK3 (circHIPK3) in diabetes-associated metabolic disorders, including hyperglycemia and insulin resistance. Results show that oleate stimulated circHIPK3 increase, and that circHIPK3 enhanced the stimulatory effect of oleate on adipose deposition, triglyceride (TG) content, and cellular glucose content in HepG2 cells. MiR-192-5p was the potential target of circHIPK3, since circHIPK3 significantly decreased miR-192-5p mRNA level, whereas anti-circHIPK3 significantly increased miR-192-5p mRNA level. Further study shows that transcription factor forkhead box O1 (FOXO1) was a downstream regulator of miR-192-5p, since miR-192-5p significantly decreased FOXO1 expression, whereas circHIPK3 significantly increased FOXO1 expression. Notably, the inhibitory effect of miR-192-5p was significantly reversed by circHIPK3. In vivo study shows that anti-miR-192-5p significantly increased blood glucose content, which was significantly inhibited by FOXO1 shRNA. MiR-192-5p significantly decreased adipose deposition and TG content in HepG2 cells, which was significantly reversed by the co-treatment with circHIPK3. Forskolin/dexamethasone (FSK/DEX) significantly increased cellular glucose, mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), and this stimulatory effect of FSK/DEX was significantly inhibited by miR-192-5p. In the presence of circHIPK3, however, the inhibitory effect of miR-192-5p was totally lost. In summary, the present study demonstrated that circHIPK3 contributes to hyperglycemia and insulin resistance by sponging miR-192-5p and up-regulating FOXO1.

MiR-542-5p Inhibits Hyperglycemia and Hyperlipoidemia by Targeting FOXO1 in the Liver

“… 28 We found that miR-542-5p is underexpressed in diabetic mice livers. As FSK/DEX has been shown to elevate cellular glucose production and expression of PEPCK and G6Pase in primary hepatocytes, 29 we verified that FSK/DEX elevated cellular glucose production and expression of PEPCK and G6Pase in primary hepatocytes and in HepG2 cells. Notably, all these stimulatory effects of FSK/DEX were remarkably counteracted by miR-542-5p.…”

Role of FoxO1 in regulating autophagy in type 2 diabetes mellitus (Review)

“…Previous studies have proposed that FoxO1 plays a significant role in the occurrence and development of insulin resistance (18,59,60). However, FoxO1 also promotes insulin resistance, which has been demonstrated in several studies (17,19,27,49). FoxO1 knockdown in HepG2-insulin resistance cells decreases the glucose content and alleviates insulin resistance in primary hepatocytes (22).…”

“…Increasing evidence suggest that FoxO1 regulates cell proliferation, apoptosis, differentiation, antioxidant stress and insulin secretion in pancreatic β-cells, and is closely associated with T2DM (13,24,25,(45)(46)(47)(48). Furthermore, FoxO1 plays a crucial role in regulating the insulin sensitivity of insulin target tissues (17,19,27,49).…”

Acute Kidney Injury in Septic Patients Treated by Selected Nephrotoxic Antibiotic Agents—Pathophysiology and Biomarkers—A Review

“…Some other experimental studies on miR-192-5p and renal diseases in association with diabetes, hypertension and drug nephrotoxicity, can be added to the complex clinical and pathophysiological review. For example, circulating RNA HIPK3 (homeodomain-interacting protein kinase 3) can bind miR-192-5p with upregulation of transcription factor FOXO1 (forkhead box protein O1) leading to hyperglycemia and insulin resistance [ 65 ]. In the kidney, miRNA-192-5p contributes to protection against hypertension through the target gene ATP1B1 (β1 subunit of Na + /K + -ATPase), and miR-192-5p levels are significantly decreased in humans with hypertension or hypertensive nephrosclerosis [ 66 ].…”