Genetic Variation in the 11β-hydroxysteroid-dehydrogenase 1 Gene Determines NAFLD and Visceral Obesity.

Abstract

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.

• Authors: Stefan Z Lutz, Andreas Peter, Fausto Machicao, Apostolia Lamprinou, Jürgen Machann, Fritz Schick, Ingmar Königsrainer, Alfred Königsrainer, Andreas Fritsche, Harald Staiger, Hans-Ulrich Häring, Norbert Stefan, Konstantinos Kantartzis
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 101 Issue 12 Pg. 4743-4751 (12 2016) ISSN: 1945-7197 [Electronic] United States
• PMID: 27715400 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• HSD11B1 protein, human

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (genetics)
• Adiposity
• Adolescent
• Adult
• Aged
• Female
• Germany
• Humans
• Insulin Resistance
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease (blood, diagnostic imaging, genetics)
• Obesity, Abdominal (blood, diagnostic imaging, genetics)
• Polymorphism, Single Nucleotide
• Proton Magnetic Resonance Spectroscopy
• Young Adult