G6PT-H6PDH-11βHSD1 triad in the liver and its implication in the pathomechanism of the metabolic syndrome

Abstract

The metabolic syndrome, one of the most common clinical conditions in recent times, represents a combination of cardiometabolic risk determinants, including central obesity, glucose intolerance, insulin resistance, dyslipidemia, non-alcoholic fatty liver disease and hypertension. Prevalence of the metabolic syndrome is rapidly increasing worldwide as a consequence of common overnutrition and consequent obesity. Although a unifying picture of the pathomechanism is still missing, the key role of the pre-receptor glucocorticoid activation has emerged recently. Local glucocorticoid activation is catalyzed by a triad composed of glucose-6-phosphate-transporter, hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase type 1 in the endoplasmic reticulum. The elements of this system can be found in various cell types, including adipocytes and hepatocytes. While the contribution of glucocorticoid activation in adipose tissue to the pathomechanism of the metabolic syndrome has been well established, the relative importance of the hepatic process is less understood. This review summarizes the available data on the role of the hepatic triad and its role in the metabolic syndrome, by confronting experimental findings with clinical observations.

Possible involvement of glucocorticoids in 5α-dihydrotestosterone-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue

“…The level of H6PDH, providing NADPH as a cofactor for 11βHSD1 activity, was unchanged in the adipose tissue of DHTtreated rats. We presume, however, that the elevation in adipose tissue CORT can still be attributed to the sustained activity of 11βHSD1, independently of H6PDH activity, owing to the greater availability of NADPH compared to NADPH + leading to predominant reductase reaction in vivo (Czegle et al, 2012). Apart from analyzing the prereceptor metabolism of glucocorticoids, we also assessed the level of GR expression and its intracellular redistribution (Nicolaides et al, 2010).…”

Gene therapy prevents hepatic tumor initiation in murine glycogen storage disease type Ia at the tumor‐developing stage

“…The major regulators of hepatic glucose metabolism are the glucocorticoids that promote gluconeogenesis and stimulate the expression of key gluconeogenic genes, G6PC and PEPCK (phosphoenolpyruvate carboxykinase) . The local (pre‐receptor) glucocorticoid activation is mediated by 11β‐hydroxysteroid dehydrogenase type 1 (11βHSD1) that converts inert cortisone (in human) and dehydrocorticosterone (in rodents) into active cortisol and corticosterone, respectively, allowing glucocorticoid receptor (GR) to be activated. Studies have shown that the expression of 11βHSD1 is downregulated in HCC .…”

Microsomal pre‐receptor cortisol production is inhibited by resveratrol and epigallocatechin gallate through different mechanisms

“…Results of both in vitro and in vivo studies show that the complex metabolism of the major stress hormone cortisol plays an important role in the pathomechanism of obesity‐related metabolic disorders . Influencing the involved enzyme activities is, therefore, considered as a novel strategy for the prevention or treatment of these diseases .…”