Hepatic 11beta-HSD1 mRNA expression in fatty liver and nonalcoholic steatohepatitis.
BACKGROUND
Nonalcoholic fatty liver disease represents the hepatic manifestation of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is the progressive form of liver injury. The pathophysiology that leads to NASH is not well understood.


OBJECTIVE
We hypothesize that an altered cortisol metabolism in the liver may be a pathogenetic factor.


METHODS
75 patients (28 men, 47 women) underwent liver biopsy for elevation in liver enzymes. Histological diagnosis identified normal liver in eight, fatty liver in 20, NASH grade 1 in 22, grade 2 in nine, grade 3 in three patients, and other forms of hepatitis or cirrhosis in 13 patients. We quantified hepatic 11beta-hydroxysteroid dehydrogenase type1 (11beta-HSD1) and hexose-6-phosphate-dehydrogenase (H6PDH) mRNA expression by real-time PCR. In addition, analysis of 24 h urinary excretion of cortisol metabolites using GCMS was performed and compared with healthy controls.


RESULTS
11beta-HSD1 mRNA expression correlated significantly (R2= 0.809; P < 0.001) with H6PDH mRNA expression, negatively with waist-to-hip ratio in women (R2= 0.394; P= 0.005), but not with urinary (THF + 5alpha-THF)/THE ratio, total cortisol metabolite excretion, age, BMI, degree of fatty liver or NASH stages. Total cortisol metabolite excretion was increased in patients with fatty liver or NASH compared with healthy controls.


CONCLUSIONS
Our data suggest that expression of hepatic 11beta-HSD1 and H6PDH are closely interlinked. 11beta-HSD1 gene expression does not seem to be involved in the pathogenesis of fatty liver or NASH. However, those patients showed an increased 5alpha- and 5beta-reduction of cortisol leading to an increased cortisol turnover rate and an activation of the HPA axis.
Konopelska
Sarah
S
Internal Medicine, Center for Gastroenterology, Hepatology, and Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
Kienitz
Tina
T
Hughes
Beverly
B
Pirlich
Matthias
M
Bauditz
Jürgen
J
Lochs
Herbert
H
Strasburger
Christian J
CJ
Stewart
Paul M
PM
Quinkler
Marcus
M
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001706:Biopsy; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*
D012333:RNA, Messenger; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone