[Show abstract][Hide abstract] ABSTRACT: Stress is the imbalance of homeostasis, which can be sensed even at the subcellular level. The stress-sensing capability of various organelles including the endoplasmic reticulum (ER) has been described. It has become evident that acute or prolonged ER stress plays an important role in many human diseases; especially those involving organs/tissues specialized in protein secretion. This article summarizes the emerging role of ER stress in diverse human pathophysiological conditions such as carcinogenesis and tumor progression, cerebral ischemia, plasma cell maturation and apoptosis, obesity, insulin resistance, and type 2 diabetes. Certain components of the ER stress response machinery are identified as biomarkers of the diseases or as possible targets for therapeutic intervention.
Full-text · Article · Nov 2007 · Annals of the New York Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: 11beta-hydroxysteroid dehydrogenase type 1, expressed mainly in the endoplasmic reticulum of adipocytes and hepatocytes, plays an important role in the prereceptorial activation of glucocorticoids. In liver endoplasmic reticulum-derived microsomal vesicles, nicotinamide adenine dinucleotide phosphate reduced supply to the enzyme is guaranteed by a tight functional connection with hexose-6-phosphate dehydrogenase and the glucose-6-phosphate transporter (G6PT). In adipose tissue, the proteins and their activities supporting the action of 11beta-hydroxysteroid dehydrogenase type 1 have not been explored yet. Here we report the occurrence of the hexose-6-phosphate dehydrogenase in rat epididymal fat, as detected at the level of mRNA, protein, and activity. In the isolated microsomes, the activity was evident only on the permeabilization of the membrane because of the poor permeability to the cofactor nicotinamide adenine dineucleotide phosphate (NADP(+)), which is consistent with the intralumenal compartmentation of both the enzyme and a pool of pyridine nucleotides. In fat cells, the access of the substrate, glucose-6-phosphate to the intralumenal hexose-6-phosphate dehydrogenase appeared to be mediated by the liver-type G6PT. In fact, the G6PT expression was revealed at the level of mRNA and protein. Accordingly, the transport of glucose-6-phosphate was demonstrated in microsomal vesicles, and it was inhibited by S3483, a prototypic inhibitor of G6PT. Furthermore, isolated adipocytes produced cortisol on addition of cortisone, and the production was markedly inhibited by S3483. The results show that adipocytes are equipped with a functional G6PT-hexose-6-phosphate dehydrogenase-11beta-hydroxysteroid dehydrogenase type 1 system and indicate that all three components are potential pharmacological targets for modulating local glucocorticoid activation.
[Show abstract][Hide abstract] ABSTRACT: 11Beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a NADP(H)-dependent oxidoreductase of the ER lumen, which may have an important role in the pathogenesis of metabolic syndrome. Here, the functional coupling of 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase (H6PDH) was investigated in rat liver microsomal vesicles. The results demonstrate the existence of a separate intraluminal pyridine nucleotide pool in the hepatic endoplasmic reticulum and a close cooperation between 11betaHSD1 and H6PDH based on their co-localization and the mutual generation of cofactors for each other.
[Show abstract][Hide abstract] ABSTRACT: The redox state of the intraluminal pyridine nucleotide pool was investigated in rat liver microsomal vesicles. The vesicles
showed cortisone reductase activity in the absence of added reductants, which was dependent on the integrity of the membrane.
The intraluminal pyridine nucleotide pool could be oxidized by the addition of cortisone or metyrapone but not of glutathione.
On the other hand, intraluminal pyridine nucleotides were slightly reduced by cortisol or glucose 6-phosphate, although glutathione
was completely ineffective. Redox state of microsomal protein thiols/disulfides was not altered either by manipulations affecting
the redox state of pyridine nucleotides or by the addition of NAD(P)+ or NAD(P)H. The uncoupling of the thiol/disulfide and NAD(P)+/NAD(P)H redox couples was not because of their subcompartmentation, because enzymes responsible for the intraluminal oxidoreduction
of pyridine nucleotides were distributed equally in smooth and rough microsomal subfractions. Instead, the phenomenon can
be explained by the negligible representation of glutathione reductase in the endoplasmic reticulum lumen. The results demonstrated
the separate existence of two redox systems in the endoplasmic reticulum lumen, which explains the contemporary functioning
of oxidative folding and of powerful reductive reactions.
Full-text · Article · Mar 2006 · Journal of Biological Chemistry