Background: Non-alcoholic fatty liver disease (NAFLD) is recognized as common liver disorder that represents the hepatic manifestation of the metabolic syndrome including visceral obesity, type 2 diabetes, insulin resistance and hyperlipidemia. Non-alcoholic steatohepatitis (NASH) is the progressive form of liver injury with the risk for progressive fibrosis, cirrhosis and end-stage liver disease. The pathophysiology that leads to NAFLD and NASH is not well understood. We hypothesize that an altered cortisol metabolism in the liver may be a pathogenetic factor. Hepatic 11beta-HSD1 regenerates cortisol from its inactive metabolite cortisone and requires NADPH as cosubstrate, which is supplied by hexose-6-phosphate-dehydrogenase (H6PDH).
Methods: 76 patients (29 men, 48 women) underwent liver biopsy due to elevated liver enzymes. We quantified 11beta-HSD1 and H6PDH mRNA expression by real-time PCR with 18S as housekeeping gene using a BioRad iCycler. In addition, anthropometric measurements and analysis of 24 hour excretion rates of glucocorticoids using gas chromatographic-mass spectrometric (GC-MS) analysis were performed.
Results: 11beta-HSD1 mRNA expression correlated significantly (r2=0.803; P<0.001) with H6PDH mRNA expression. We detected a significant correlation between 11beta-HSD1 mRNA expression and waist-to-hip ratio (r2=0.211; P<0.05), but not to urinary (THF+5alphaTHF)/THE ratio, total cortisol metabolite excretion, age or BMI. No gender specific differences were seen in mRNA gene expression.
Discussion: Our data suggest that 11beta-HSD1 gene expression highly depends on H6PDH gene expression. Surprisingly, 11beta-HSD1 gene expression did not correlate with any urinary glucocorticoid ratio showing the limitation of urinary analysis. In our patients cohort a higher waist-to-hip-ratio (abdominal obesity) was associated with a lower 11beta-HSD1 mRNA expression in the liver.