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Identification of matrine as a promising novel drug for hepatic steatosis and glucose intolerance with HSP 72 as an upstream target
Author(s) -
Zeng XiaoYi,
Wang Hao,
Bai Fang,
Zhou Xiu,
Li SongPei,
Ren LuPing,
Sun RuoQiong,
Xue Charlie C L,
Jiang HuaLiang,
Hu LiHong,
Ye JiMing
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13209
Subject(s) - matrine , metformin , steatosis , triglyceride , insulin resistance , medicine , endocrinology , fatty liver , type 2 diabetes , lipid metabolism , metabolic syndrome , nonalcoholic fatty liver disease , insulin , pharmacology , chemistry , diabetes mellitus , cholesterol , disease , psychiatry
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 / J 6 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 HSP 90, a negative regulator of HSP 72, as a potential binding target of matrine. Consistent with the simulation results, matrine, but not metformin, increased the hepatic protein level of HSP 72 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 HSP 72 in the liver.