Compound Danshen Dripping Pills Prevented Leptin Deficiency-Induced Hepatic ER Stress, Stimulated Autophagy, and Improved Insulin Resistance of ob/ob Mice

Yanan Shi, Dan Liu, Jihong Yuan, Lihui Yan, Zhenfeng Zhan, Da Pan, Laixiang Lin, Biao Mu, Yanan Shi, Dan Liu, Jihong Yuan, Lihui Yan, Zhenfeng Zhan, Da Pan, Laixiang Lin, Biao Mu

Abstract

Compound Danshen dripping pills (CDDP) is widely used for the treatment of coronary arteriosclerosis and ischemic heart diseases for decades of years. In our study, we interestingly discovered the effects and mechanism of CDDP on insulin resistance that increase the risk factor of cardiovascular diseases. Effects of CDDP on fasting blood glucose, the insulin tolerance test (ITT), the oral glucose tolerance test (OGTT), hepatic function, and underlying mechanism were analyzed in ob/ob mice. CDDP was found improving the impaired insulin signal sensitivity of ob/ob mice by ameliorating insulin and glucose tolerance, improving hepatic phosphorylation of the insulin receptor substrate-1 on Ser 307 (pIRS1) of ob/ob mice, and restoring hepatic function by decreasing serum ALT and AST, which increased in ob/ob mice serum. Decreasing hepatic phosphorylation of pancreatic ER kinase (PERK) and inositol-requiring enzyme-1 (IRE1) regulating hepatic ER stress in the liver of ob/ob mice were increased by CDDP. Furthermore, CDDP was also found stimulating ob/ob mice hepatic autophagy by increasing the expression of Beclin1 and LC3B, while decreasing P62 expression. Our study discovered an important role of CDDP on improving ob/ob mice insulin resistance and liver function probably through relieving hepatic ER stress and stimulating hepatic autophagy, which would broaden the application value and provide more benefits for treating cardiovascular patients. This trial is registered with NCT01659580.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Copyright © 2020 Yanan Shi et al.

Figures

Figure 1
Figure 1
The effect of CDDP on insulin resistance and the liver function. Insulin tolerance (a) and serum AST, ALT, and ALP (b) were measured between the control mice and ob/ob mice. The insulin tolerance test (c), serum AST, ALT, and ALP (d), fasting blood glucose (e), and glucose tolerance test (f) were performed between two groups. The blood glucose was measured and compared at the indicated time point (a), (c), and (f). ∗p < 0.05, compared to the control mice (a) and (b) and compared to the ob/ob mice (c)–(f)).
Figure 2
Figure 2
CDDP improved hepatic insulin signal sensitivity. (a) The insulin signaling marker IRS1 Ser307 phosphorylation in the liver was compared between the control mice and ob/ob mice. (b) CDDP-regulated hepatic phosphorylation of IRS1 serine 307 was of ob/ob mice. ∗p < 0.05, compared to the control mice for (a) and compared to ob/ob mice for (b).
Figure 3
Figure 3
CDDP reduced hepatic ER stress induced in the liver of ob/ob mice. The expressions of ER stress markers including phosphorylated PERK Tyr980 and IRE1 Ser742 were measured and compared between the control and ob/ob mice (a) and (b) and between ob/ob and CDDP-treated mice (c) and (d). ∗p < 0.05, compared to the control mice for (a) and (b) and compared to ob/ob mice for (c) and (d).
Figure 4
Figure 4
CDDP increased hepatic autophagy inhibited in the liver of ob/ob mice. Hepatic expressions of Beclin 1, LC3B, and P62 were measured and compared between the control and ob/ob mice (a) and between ob/ob and CDDP-treated mice (b). ∗p < 0.05, compared to the control mice for (a) and (b) and compared to ob/ob mice for (c) and (d).

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Source: PubMed

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