Endocrine Abstracts

The endoplasmic reticulum (ER) is a metabolic compartment participating in virtually all anabolic and catabolic branches of cellular metabolism. The redox balance of pyridine nucleotides is a major regulator of the metabolism. Several observations demonstrate their presence in the lumen of the ER. NADPH donates electrons for biosynthetic reactions, biotransformation and antioxidant defense; its reduced state is ensured by NADP⁺-dependent dehydrogenases. In the ER lumen, hexose-6-phosphate dehydrogenase (H6PDH) seems to be the sole (or at least the major) NADPH generating enzyme. It is not inhibited by steroids or NADPH, therefore it can maintain a high [NADPH]/[NADP⁺] ratio in the ER lumen, suitable for the reduction (and activation) of hydroxysteroids.

The aim of our work was to investigate the redox homeostasis of the ER lumen, with special regard to the functioning of the glucose-6-phosphate transporter (G6PT) – H6PDH – 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) triad. We observed that luminal pyridine nucleotides are dominantly reduced, which means that they are uncoupled from the rather oxidized thiol/disulfide system. The separate pyridine nucleotide pool of the ER is the biochemical basis of the cooperation between H6PDH and 11βHSD1. The maintenance of the reduced state of NADPH is required for the prereceptorial glucocorticoid activation, for the induction of 11βHSD1 during adipogenesis and for the antioxidant defense of the lumen. It can be supposed that the unidirectionality of other hydroxysteroid dehydrogenases is also based on the intraluminal localization in the ER.

A role in nutrient sensing can also be postulated to the above system. Overnutrition (excess of reducing power) causes the elevation of intracellular glucose-6-phosphate level which activates H6PDH via G6PT. The generated and maintained high [NADPH]/[NADP⁺] ratio in the ER lumen supports glucocorticoid activation by 11βHSD1. High local glucocorticoid levels counter-regulate insulin action and promote nutrient storage, hence producing the most characteristic features of the metabolic syndrome.