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Journal of Chinese Integrative Medicine ›› 2012, Vol. 10 ›› Issue (7): 793-799.doi: 10.3736/jcim20120710

• Original Experimental Research • Previous Articles     Next Articles

Effects of ursolic acid in ameliorating insulin resistance in liver of KKAy mice via peroxisome proliferator-activated receptors α and γ

Lin Wang1, Guan-liang Wang1, Jia-han Liu1, Di Li1, De-zeng Zhu1(), Liang-neng Wu2()   

  1. 1. Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
    2. School of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, China
  • Received:2011-12-19 Accepted:2012-01-28 Online:2012-07-20 Published:2018-07-15
  • Contact: De-zeng Zhu,Liang-neng Wu E-mail:zdzzyx@163.com;wuliangnen@sina.com

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Objective: To explore the effects and mechanism of ursolic acid in improving hepatic insulin resistance in KKAy mice with spontaneous type 2 diabetes.
Methods: Thirty-five KKAy mice were divided into five groups according to the randomized block design, namely, control, rosiglitazone, fenofibrate, and high- and low-dose ursolic acid groups with seven mice in each group. C57BL/6J mice were used as the normal control group. At the end of the 4th week, free fatty acid (FFA), tumor necrosis factor-α (TNF-α) and adiponectin contents in serum were detected by enzyme-linked immunosorbent assay; the protein expressions of phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor substrate-2 (IRS-2) and glucose transport factor-2 (GLUT-2) were detected by Western blot method; the mRNA expressions of PEPCK, IRS-2 and GLUT-2 were detected by real-time polymerase chain reaction; the expressions of peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ) in liver tissue were detected by immunohistochemical method.
Results: After four weeks of intervention, the contents of FFA, TNF-α and adiponectin in serum of the high-dose ursolic acid group had changed, showing statistically significant difference compared to those of the control group (P<0.01); high dose of ursolic acid had depressant effect on the expressions of PEPCK protein and PEPCK mRNA (P<0.01); low dose of ursolic acid depressed the expression of PEPCK mRNA and induced phosphorylation of IRS-2 in the liver (P<0.05); both high and low dose of ursolic acid improved the expression of PPARα in the liver (P<0.01).
Conclusion: The effects of ursolic acid in improving hepatic insulin resistance in KKAy mice with spontaneous type 2 diabetes may be closely related to affecting the contents of FFA, TNF-α and adiponectin, improving the expression of PPARα protein, regulating transcription of PEPCK protein and inducing phosphorylation of IRS-2.

Key words: hypoglycemic agents (TCD), ursolic acid, PPARα, PPARγ, insulin resistance, diabetes mellitus, experimental, procetofen, mice

Table 1

Levels of serum FFA, TNF-α and adiponectin in different groups (x±s)"

Group n FFA (μmol/L) TNF-α (ng/L) Adiponectin (mg/L)
Normal 7 74.33±7.69**△△▲▲ 78.64±1.16** 19.52±0.09**△△
Control 7 427.32±9.31▲▲ 133.45±1.60△△ 4.13±0.12▲▲
Rosiglitazone 7 352.68±9.15▲▲ 92.74±1.86** 6.77±0.06*
Fenofibrate 6 192.54±85.48**△△ 103.85±1.61** 10.19±0.37**△
UA 300 mL/(kg·d) 7 250.29±8.08*△ 105.42±1.27* 6.82±0.10▲
UA 150 mL/(kg·d) 6 341.45±151.41▲▲ 131.85±1.97△△ 5.79±0.05▲

Figure 1

IRS-2 phosphorylation and expressions of PEPCK and GLUT-2 proteins in liver tissues of different groups Data are represented as x±s, n=3. *P<0.05, **P<0.01, vs control group; △P<0.05, △△P<0.01, vs rosiglitazone group. NOR: Normal group; CON: Control group; ROS: Rosiglitazone group; FEN: Fenofibrate group; UA300: High-dose ursolic acid (300 mL/(kg·d)) group; UA150: low-dose ursolic acid (150 mL/(kg·d)) group. PEPCK: phosphoenolpyruvate carboxykinase; GLUT-2: glucose transport factor-2; IRS-2: insulin receptor substrate-2."

Table 2

Expressions of PEPCK, IRS-2 and GLUT-2 mRNAs in liver tissues of each group (x±s, %)"

Group n PEPCK GLUT-2 IRS-2
Normal 7 10.86±1.15** 15.04±0.88** 5.41±0.57**
Control 7 18.37±1.29△△ 10.20±1.49 1.23±0.34
Rosiglitazone 7 12.45±1.26** 11.63±0.83 1.63±0.17
Fenofibrate 6 15.97±1.47 13.59±0.95 1.34±0.12
UA 300 mL/(kg·d) 7 13.02±0.95**△ 11.15±1.33 2.38±0.27
UA 150 mL/(kg·d) 6 14.18±0.92* 12.72±1.09 2.39±0.21

Table 3

Expressions of PPARα and PPARγ proteins observed by quantitative immunohistochemical staining in liver tissues of each group (x±s)"

Group n PPARα PPARγ
Normal 3 3.73±0.21** 2.78±0.13
Control 3 1.53±0.15▲▲ 2.61±0.36
Rosiglitazone 3 1.84±0.26▲ 3.04±0.21
Fenofibrate 3 2.21±0.27**△△ 3.13±0.38
UA 300 mL/(kg·d) 3 3.10±0.34**△△ 2.72±0.07
UA 150 mL/(kg·d) 3 3.07±0.22**△△ 3.06±0.31

Figure 2

Expressions of PPARα and PPARγ proteins detected by immunohistochemical method in liver tissues of different groups （Light microscopy, ×250） NOR: Normal group; CON: Control group; ROS: Rosiglitazone group; FEN: Fenofibrate group; UA300: High-dose ursolic acid (300 mL/(kg·d)) group; UA150: low-dose ursolic acid (150 mL/(kg·d)) group. PPAR: peroxisome proliferator-activated receptor."

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