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Lutz, S.Z. ; Peter, A. ; Machicao, F. ; Lamprinou, A. ; Machann, J. ; Schick, F. ; Königsrainer, I.* ; Königsrainer, A.* ; Fritsche, A. ; Staiger, H. ; Häring, H.-U. ; Stefan, N. ; Kantartzis, K.

Genetic variation in the 11β-hydroxysteroid-dehydrogenase 1 gene determines NAFLD and visceral obesity.

J. Clin. Endocrinol. Metab. 101, 4743-4751 (2016)
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CONTEXT/OBJECTIVE: Acute pharmacological inhibition of 11β-hydroxysteroid-dehydrogenase 1 (11β-HSD1), which converts cortisone into the much more potent cortisol in peripheral tissues, results in reduction of total, visceral, and liver fat but not insulin resistance. We now investigated whether lifelong alterations of 11β-HSD1 activity similarly affect these cardiometabolic risk parameters by studying single-nucleotide polymorphisms (SNPs) in the 11β-HSD1-coding gene (HSD11B1). DESIGN/METHODS: Liver fat content was measured by 1H-magnetic resonance spectroscopy and total and visceral fat mass by 1H-magnetic resonance tomography in 327 subjects. Insulin sensitivity (IS) was estimated during an oral glucose tolerance test and the euglycemic, hyperinsulinemic clamp (n = 219). Nine SNPs covering the whole HSD11B1 gene were genotyped. RESULTS: After correction for multiple testing, liver fat content strongly correlated with three SNPs, rs2235543, rs12565406, and rs4844880 (P = .0002, P = .001, and P = .0009, respectively), independently of gender and age. There was a nominal association of these SNPs with hepatic IS but only of rs4844880 with whole-body IS. Subjects homozygous for the major allele had an adjusted odds ratio of 2.16 (95% confidence interval [CI] 1.23-3.90) for rs2235543, 2.06 (95% CI 1.08-4.13) for rs12565406, and 1.95 (95% CI 1.13-3.49) for rs4844880 for having nonalcoholic fatty liver disease compared with carriers of the minor allele. Less strong associations of these SNPs with visceral fat mass were observed. In liver biopsies, carriers of the minor alleles of rs2235543 and rs12565406 had significantly lower HSD11B1 mRNA expression (n = 105, P = .034 and P = .0086, respectively). CONCLUSIONS: 11β-HSD1 may be an important enzyme in the pathogenesis of fatty liver and visceral obesity and a promising target for their treatment.  
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Nonalcoholic Fatty Liver; Hydroxysteroid Dehydrogenase Type-1; Splanchnic Cortisol Production; Metabolic Syndrome; Adipose-tissue; Insulin-resistance; Mendelian Randomization; 11-beta-hsd1 Gene; Glucose-tolerance; Diabetes-mellitus
ISSN (print) / ISBN 0021-972X
e-ISSN 1945-7197
Journal Journal of Clinical Endocrinology & Metabolism, The
Quellenangaben Volume: 101, Issue: 12, Pages: 4743-4751 Article Number: , Supplement: ,
Publisher Endocrine Society
Publishing Place Bethesda, Md.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)