Identification of matrine as a promising novel drug for hepatic steatosis and glucose intolerance with HSP72 as an upstream target - PubMed (original) (raw)
. 2015 Sep;172(17):4303-18.
doi: 10.1111/bph.13209. Epub 2015 Jul 14.
Affiliations
- PMID: 26040411
- PMCID: PMC4556469
- DOI: 10.1111/bph.13209
Identification of matrine as a promising novel drug for hepatic steatosis and glucose intolerance with HSP72 as an upstream target
Xiao-Yi Zeng et al. Br J Pharmacol. 2015 Sep.
Abstract
Background and purpose: Matrine is a small molecule drug used in humans for the treatment of chronic viral infections and tumours in the liver with little adverse effects. The present study investigated its therapeutic efficacy for insulin resistance and hepatic steatosis in high-fat-fed mice.
Experimental approach: C57BL/J6 mice were fed a chow or high-fat diet for 10 weeks and then treated with matrine or metformin for 4 weeks. The effects on lipid metabolism and glucose tolerance were evaluated.
Key results: Our results first showed that matrine reduced glucose intolerance and plasma insulin level, hepatic triglyceride content and adiposity in high-fat-fed mice without affecting caloric intake. This reduction in hepatosteatosis was attributed to suppressed lipid synthesis and increased fatty acid oxidation. In contrast to metformin, matrine neither suppressed mitochondrial respiration nor activated AMPK in the liver. A computational docking simulation revealed HSP90, a negative regulator of HSP72, as a potential binding target of matrine. Consistent with the simulation results, matrine, but not metformin, increased the hepatic protein level of HSP72 and this effect was inversely correlated with both liver triglyceride level and glucose intolerance.
Conclusions and implications: Taken together, these results indicate that matrine may be used for the treatment of type 2 diabetes and hepatic steatosis, and the molecular action of this hepatoprotective drug involves the activation of HSP72 in the liver.
© 2015 The British Pharmacological Society.
Figures
Figure 1
Matrine improved fasting blood glucose, plasma insulin and glucose tolerance in HF-fed mice. Molecular structure of matrine (A). Ten-week-old C57BL/6J mice were fed with a CH or a HF diet for 14 weeks. Matrine or metformin was administered for the last 4 weeks. After drug treatment, blood glucose (B) and plasma insulin (C) were measured following a 5–7 h fast. Blood glucose (D) and plasma insulin (E) were monitored in an i.p. GTT (glucose dose, 1 g·kg−1) after the 2 week drug treatment. iAUC of blood glucose (F). AUC of plasma insulin (G). Whole-body insulin index (H) was expressed as blood glucose AUC × plasma insulin AUC. Data are mean ± SEM. *P < 0.05, **P < 0.01 versus CH-Veh; †P < 0.05, ††P < 0.01 versus HF-Veh. a_P_ < 0.05, CH-Veh versus HF-Veh; b_P_ < 0.05, CH-Veh versus CH-Mtr; c_P_ < 0.05, HF-Veh versus HF-Mtr. n = 8 per group.
Figure 2
Matrine reduced lipid accumulation and inflammation in the liver with a suppression of the lipid synthesis pathway. Liver and muscle triglyceride levels and the phosphorylation status of PKCϵ in the liver were measured after drug treatment (A). Representative H&E staining (400×) images of liver sections. Scale bar, 150 μm (B). Gene expressions of TNFα (C), IL-1β (D) and IL-6 (E) in the liver. The phosphorylation status of JNK and IKKα/β (F). Protein expression of SREBP-1 (G) in the nuclear fraction of the liver. Protein levels of ACC, FAS and SCD-1 (H) in the liver. Data are mean ± SEM. *P < 0.05, **P < 0.01 versus CH-Veh; †P < 0.05, ††P < 0.01 versus HF-Veh, n = 8 per group.
Figure 3
Matrine increased energy expenditure and promoted fatty acid utilization as the energy source. Protein expression of UCP2 in the liver of CH- or HF-fed mice treated with matrine or metformin (A). Activities of CS and β-hydroxyacyl-CoA dehydrogenase (β-HAD) isolated from the liver. Data are mean ± SEM. *P < 0.05 versus CH-Veh; †P < 0.05 versus HF-Veh, n = 8 per group (B,C). Palmitate oxidation in liver homogenate from CH-fed mice was determined with [1-14C]-palmitate. *P < 0.05 versus vehicle, n = 2–4 per group from four independent experiments (D). Oxygen consumption (E) and RER (F) of CH-fed mice were monitored for 7 h after administration of vehicle (0.5% methylcellulose), matrine or metformin by oral gavage. *P < 0.05 versus CH-Veh, n = 5–9 per group.
Figure 4
Effects of matrine did not involve altered mitochondria electron transport chain, or activation of AMPK or PPARα. Oxygen consumption rates were measured in isolated mitochondria from CH-fed mice at 37°C. n = 3 per group (A). The phosphorylation status of AMPK and ACC (B) and the protein expression of ACOX1 (C) in the liver after drug treatment. Data are mean ± SEM. *P < 0.05 versus CH-Veh, n = 8 per group.
Figure 5
Matrine up-regulated hepatic HSP72 expression, which is associated with liver triglyceride and glucose tolerance. The binding pose of matrine or metformin to HSP90 was predicted by molecular docking simulation. The lilac cartoon represents HSP90, the violet stick models are important amino acid residues, red spheres are conserved water molecules, the dash lines represent hydrogen bonds and the orange stick-ball models are matrine or metformin (A). Protein levels of HSP72, HSP90, HSF1, GSK3β and ERK in the liver after drug treatment (B). Correlation of hepatic HSP72 expression with liver triglyceride or iAUC of blood glucose (C). Illustration of matrine-mediated reduction of lipid accumulation and improvement of glucose tolerance (D). Data are mean ± SEM. *P < 0.05 versus CH-Veh; †P < 0.05 versus HF-Veh, n = 8 per group.
References
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