Inhibition of microsomal cortisol production by (–)-epigallocatechin-3-gallate through a redox shift in the endoplasmic reticulum — A potential new target for treating obesity-related diseases

摘要

Conversion of cortisone to cortisol by 11β-hydroxysteroid uddehydrogenase type 1 (11βHSD1) in the endoplasmic reticulum (ER) udof the target cells is a major determinant of glucocorticoid udaction, and plays an important role in the development of udobesity-related diseases. Inhibition of 11βHSD1 activity is, udtherefore, considered as a promising novel strategy for the udtreatment of metabolic syndrome and diabetes. Tea flavanols and udtheir major representative, epigallocatechin gallate are known udas antiobesity and antidiabetic agents. Their impacts on blood udglucose level, hepatic glucose production, and insulin udresponsiveness resemble those observed on inhibition or uddepletion of 11βHSD1. We aimed to study the effect of udepigallocatechin gallate on 11βHSD1 activity in ER-derived rat udliver microsomes by measuring cortisone and cortisol with HPLC. udCortisol production was efficiently suppressed in a udconcentration dependent manner in intact microsomal vesicles. udHowever, this effect was abolished by membrane permeabilization; udand the three proteins involved in the overall process (11βHSD1, udhexose 6-phosphate dehydrogenase, and glucose 6-phosphate udtransporter) were not or only mildly affected. Further udinvestigation revealed the oxidation of luminal NADPH to NADP+, udwhich attenuates cortisone reduction and favors cortisol udoxidation in this compartment. Such a redox shift in the ER udlumen might contribute to the beneficial health effects of tea udflavanols and should be regarded as a promising strategy for the uddevelopment of novel selective 11βHSD1 inhibitors to treat udobesity-related diseases. © 2013 BioFactors 39(5):534–541, 2013