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| Carboxylesterases constitute a class of enzymes that hydrolyze drugs containing such functional groups as esters, amides, thioesters and carbamates. Ljver has abundant carboxylesterases expression, however, the alteration of carboxylesterases in type 2 diabetes remains to be elucidated. In this study, type 2 diabetic (T2D) mice were prepared by combination of high-fat diet and streptozocin (STZ) injection. We found that the carboxylesterase 1d (Ces1d, CES1) and carboxylesterase 1e (Ces1e, CES2) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1α/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could come out the same results in high glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. Perifosine or rapamycin almost abolished the decreases of Ces1d and Ces1e expression and hydrolytic activity induced by insulin in the primary mouse hepatocytes. Moreover, the responsiveness of human hepatoma (HepG2) cells to high insulin in high glucose condition was similar to the primary mouse hepatocytes in terms of altered expression of carboxylesterases. Knockdown of HIF-1α or DEC1 with shRNA construct abrogated the decreases of CES1 and CES2 expression induced by insulin. The data suggest that the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through Akt/mTOR/HIF-1α/Stra13 (DEC1) pathway. The findings will contribute to guide rational use of drugs in type 2 diabetic patients. |
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| Keywords: carboxylesterase 1(CES1, Ces1d); carboxylesterase 2 (CES2, Ces1e); Type 2 diabetes; insulin; Akt/mTOR/HIF-1α/ Stra13 pathway |
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