Kivonat:
Conversion of cortisone to cortisol by 11β-hydroxysteroid
dehydrogenase type 1 (11βHSD1) in the endoplasmic reticulum (ER)
of the target cells is a major determinant of glucocorticoid
action, and plays an important role in the development of
obesity-related diseases. Inhibition of 11βHSD1 activity is,
therefore, considered as a promising novel strategy for the
treatment of metabolic syndrome and diabetes. Tea flavanols and
their major representative, epigallocatechin gallate are known
as antiobesity and antidiabetic agents. Their impacts on blood
glucose level, hepatic glucose production, and insulin
responsiveness resemble those observed on inhibition or
depletion of 11βHSD1. We aimed to study the effect of
epigallocatechin gallate on 11βHSD1 activity in ER-derived rat
liver microsomes by measuring cortisone and cortisol with HPLC.
Cortisol production was efficiently suppressed in a
concentration dependent manner in intact microsomal vesicles.
However, this effect was abolished by membrane permeabilization;
and the three proteins involved in the overall process (11βHSD1,
hexose 6-phosphate dehydrogenase, and glucose 6-phosphate
transporter) were not or only mildly affected. Further
investigation revealed the oxidation of luminal NADPH to NADP+,
which attenuates cortisone reduction and favors cortisol
oxidation in this compartment. Such a redox shift in the ER
lumen might contribute to the beneficial health effects of tea
flavanols and should be regarded as a promising strategy for the
development of novel selective 11βHSD1 inhibitors to treat
obesity-related diseases. © 2013 BioFactors 39(5):534–541, 2013
