ContextNon alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH) and cirrhosis. The potential role of glucocorticoids (GC) in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol (F) from inactive cortisone (E) (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1), or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR).Objective and MethodsIn vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone.ResultsIn patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa.ConclusionPatients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11β-HSD1 activity and consequent cortisol regeneration may serve to limit hepatic inflammation.

Microsomal glucose-6-phosphatase-␣ (G6Pase-␣) and glucose 6-phosphate transporter (G6PT) work together to increase blood glucose concentrations by performing the terminal step in both glycogenolysis and gluconeogenesis. Deficiency of the G6PT in liver gives rise to glycogen storage disease type 1b (GSD1b), whereas deficiency of G6Pase-␣ leads to GSD1a. G6Pase-␣ shares its substrate (glucose 6-phosphate; G6P) with hexose-6-phosphate-dehydrogenase (H6PDH), a microsomal enzyme that regenerates NADPH within the endoplasmic reticulum lumen, thereby conferring reductase activity upon 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1). 11␤-HSD1 interconverts hormonally active C11␤-hydroxy steroids (cortisol in humans and corticosterone in rodents) to inactive C11-oxo steroids (cortisone and 11-dehydrocorticosterone, respectively). In vivo reductase activity predominates, generating active glucocorticoid. We hypothesized that substrate (G6P) availability to H6PDH in patients with GSD1b and GSD1a will decrease or increase 11␤-HSD1 reductase activity, respectively. We investigated 11␤-HSD1 activity in GSD1b and GSD1a mice and in two patients with GSD1b and five patients diagnosed with GSD1a. We confirmed our hypothesis by assessing 11␤-HSD1 in vivo and in vitro, revealing a significant decrease in reductase activity in GSD1b animals and patients, whereas GSD1a patients showed a marked increase in activity. The cellular trafficking of G6P therefore directly regulates 11␤-HSD1 reductase activity and provides a novel link between glucose metabolism and function of the hypothalamo-pituitary-adrenal axis.

Glucose infusion into rats has been shown to sensitize/ desensitize insulin secretion in response to glucose. In pancreatic islets from glucose-infused rats (GIR) (48 h, 50%, 2 ml/h) basal insulin release (2·8 mmol/l glucose) was more than fourfold compared with islets from salineinfused controls and the concentration-response curve for glucose was shifted to the left with a maximum at 11·1 mmol/l. The concentration-response curve for 45 Ca 2+ uptake was also shifted to the left in islets from GIR with a maximum at 11·1 mmol/l glucose. Starting from a high basal level at 2·8 mmol/l glucose KCl produced no insulin release or 45 Ca2+ uptake in islets from GIR. Islets from GIR exhibited a higher ATP/ADP ratio in the presence of 2·8 mmol/l glucose and marked inhibition of 86 Rb + efflux occurred even at 3 mmol/l glucose. Moreover, in islets from GIR the redox ratios of pyridine nucleotides were increased. On the other hand insulin content was reduced to about 20%.The data suggest that a 48-h glucose infusion sensitizes glucose-induced insulin release in vitro in concentrations below 11·1 mmol/l. This may, at least in part, be due to enhanced glucose metabolism providing increased availability of critical metabolic factors including ATP which, in turn, decrease the threshold for depolarization and therefore calcium uptake. Calcium uptake may then be further augmented by elevation of the redox state of pyridine nucleotides.

These results indicate significant induction of HSD11B1 gene expression and activity in patients with ALD during short- and long-term abstinence from alcohol. The mechanism is unknown but might be explained on the basis of alcohol-induced changes in intracellular redox potential or as a protective mechanism to limit liver inflammation and injury. Selective 11beta-HSD1 inhibitors may offer a novel therapeutic approach to treat alcoholic pseudo-Cushing's.