Overexpression of 11β‐hydroxysteroid dehydrogenase type 1 in visceral adipose tissue and portal hypercortisolism in non‐alcoholic fatty liver disease

Abstract

The enzyme 11β-hydroxysteroid-dehydrogenase type 1 (11β-HSD1) catalyses the reactivation of intracellular cortisol. We explored the potential role of 11β-HSD1 overexpression in visceral adipose tissue (VAT) in non-alcoholic fatty liver disease (NAFLD) assessing sequential changes of enzyme expression, in hepatic and adipose tissue, and the occurrence of portal hypercortisolism in obese mice. 11β-HSD1 expression was also assessed in tissues from obese patients undergoing bariatric surgery. Peripheral and portal corticosterone levels and liver histology were assessed in ob/ob mice at two time points (8-12weeks of age). 11β-HSD1 tissue expression was assessed in by RT-pcr in ob/ob mice and in 49 morbidly obese patients. Portal corticosterone serum levels were higher in obese mice with a 26% decrease between 8 and 12weeks of age (controls: 78.3 ±19.7ng/ml, 8-week-old ob/ob: 167.5±14.5ng/ml and 12-week-old ob/ob: 124.3±28ng/ml, P<0.05). No significant differences were found in peripheral corticosterone serum levels. Expression of 11β-HSD1 was lower in the liver [-45% at 8weeks and -35% at 12-weeks (P=0.0001)] and highly overexpressed in VAT in obese mice, compared to controls (128-fold higher in 8-week-old ob/ob and 41-fold higher in 12-week-old ob/ob, P<0.01). No significant differences were seen in the expression of 11β-HSD1 in subcutaneous adipose tissue. In multivariate analysis, human 11β-HSD1 expression in VAT (OR: 1.385±1.010-1.910) was associated with NAFLD. Murine NAFLD is associated with portal hypercortisolism and11β-HSD1 overexpression in VAT. In humans, 11β-HSD1 VAT expression was associated with the presence of NAFLD. Thus, local corticosteroid production in VAT may contribute to NAFLD pathogenesis.