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

Lutz, Stefan; Machicao, Fausto; Lamprinou, Apostolia; Machann, Jürgen; Schick, Fritz; Königsrainer, Ingmar; Königsrainer, Alfred; Fritsche, Andreas; Staiger, Harald; Häring, Hans‐Ulrich; Stefan, Norbert; Kantartzis, Kοnstantinos

doi:10.1210/jc.2016-2498

Cited by 21 publications

(19 citation statements)

References 41 publications

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“…Studies of the HSD11B1 gene are conflicted regarding a relationship with metabolic disease. Polymorphisms in the HSD11B1 gene are associated with fatty liver and type 2 diabetes (T2D) with or without metabolic syndrome [12,37,38]. Adipose HSD11B1 expression and activity are sometimes seen to correlate with insulin resistance or polycystic ovary syndrome [39][40][41][42][43]; while other studies show HSD11B1 expression correlates with obesity rather than metabolic disease [38,44], and the relationship between gene expression and fasting insulin may vary depending on tissue bed [45].…”

Section: Discussionmentioning

confidence: 99%

“…The link between increased adipose glucocorticoid action and ectopic lipid deposition is supported by several studies. In humans, single nucleotide polymorphisms in the HSD11B1 gene are associated with changes in hepatic fat deposition [12]. Whole-body pharmacologic HSD11B1 inhibition in mice reduces hepatic steatosis, though this has been attributed to potentially increased hepatic lipid oxidation [13].…”

Section: Introductionmentioning

confidence: 99%

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Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice

et al. 2019

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Context: Excessive adipose glucocorticoid action is associated with insulin resistance, but the mechanisms linking adipose glucocorticoid action to insulin resistance are still debated. We hypothesized that insulin resistance from excess glucocorticoid action may be attributed in part to increased ectopic lipid deposition in liver. Methods: We tested this hypothesis in the adipose specific 11β-Hydroxysteroid dehydrogenase-1 (HSD11B1) transgenic mouse, an established model of adipose glucocorticoid excess. Tissue specific insulin action was assessed by hyperinsulinemic-euglycemic clamps, hepatic lipid content was measured, hepatic insulin signaling was assessed by immunoblotting. The role of hepatic lipid content was further probed by administration of the functionally liver-targeted mitochondrial uncoupler, Controlled Release Mitochondrial Protonophore (CRMP). Findings: High fat diet fed HSD11B1 transgenic mice developed more severe hepatic insulin resistance than littermate controls (endogenous suppression of hepatic glucose production was reduced by 3.8-fold, P < 0.05); this was reflected by decreased insulin-stimulated hepatic insulin receptor kinase tyrosine phosphorylation and AKT serine phosphorylation. Hepatic insulin

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice

et al. 2019

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“…When stratifying the sample either by the presence of obesity or MetS, in both groups we have found an inverse relationship between abdominal adipose tissue HSD11B1 gene expression and BMI, but this relationship remained significant only in those with obesity. Lutz et al investigated the expression of nine different polymorphisms for the HSD11B1 gene in a total of 327 German patients [45]. The major C allele of rs2235543 and the major G allele of rs12565406 were significantly associated with increased VAT mass.…”

Section: Discussionmentioning

confidence: 99%

Interaction of HSD11B1 and H6PD polymorphisms in subjects with type 2 diabetes are protective factors against obesity: a cross-sectional study

Chedid

Nascimento

Oliveira

et al. 2019

Diabetol Metab Syndr

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Background The enzyme 11-beta hydroxysteroid dehydrogenase type 1 (HSD11B1) converts inactive cortisone to active cortisol in a process mediated by the enzyme hexose-6-phosphate dehydrogenase (H6PD). The generation of cortisol from this reaction may increase intra-abdominal cortisol levels and contribute to the physiopathogenesis of obesity and metabolic syndrome (MetS). The relationship of HSD11B1 rs45487298 and H6PD rs6688832 polymorphisms with obesity and MetS was studied. We also studied how HSD11B1 abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) gene expression is related to body fat distribution. Methods Rates of obesity and MetS features were cross-sectionally analyzed according to these polymorphisms in 1006 Brazilian white patients with type 2 diabetes (T2DM). Additionally, HSD11B1 expression was analyzed in VAT and SAT in a different cohort of 28 participants with and without obesity who underwent elective abdominal operations. Results Although polymorphisms of the two genes were not individually associated with MetS features, a synergistic effect was observed between both. Carriers of at least three minor alleles exhibited lower BMI compared to those with two or fewer minor alleles adjusting for gender and age (27.4 ± 4.9 vs. 29.3 ± 5.3 kg/m2; P = 0.005; mean ± SD). Obesity frequency was also lower in the first group (24.4% vs. 41.6%, OR = 0.43, 95% CI 0.21–0.87; P = 0.019). In the second cohort of 28 subjects, HSD11B1 gene expression in VAT was inversely correlated with BMI (r = − 0.435, P = 0.034), waist circumference (r = − 0.584, P = 0.003) and waist-to-height ratio (r = − 0.526, P = 0.010). Conclusions These polymorphisms might interact in the protection against obesity in T2DM individuals. Obese individuals may have decreased intra-abdominal VAT HSD11B1 gene expression resulting in decreasing intra-abdominal cortisol levels as a compensatory mechanism against central and general adiposity.

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“…Moreover, 11-HSD1 activity and/or expression of the corresponding HSD11B1 mRNA are increased in both visceral and subcutaneous adipose tissue in obese human subjects in most [13-15] but not all [16] studies and do not decrease with weight reduction [13] suggesting that increased HSD11B1 expression may be causally related to obesity in humans. Finally, there are strong associations between certain single nucleotide polymorphisms in HSD11B1 and both liver fat content and the risk of developing nonalcoholic fatty liver disease [17], and also associations between other polymorphisms and serum alanine aminotransferase levels [18]. The mechanisms underlying these associations are not known.…”

Section: Functional Roles Of 11-hsd1mentioning

confidence: 99%

Alterations of Cortisol Metabolism in Human Disorders

White

2018

Horm Res Paediatr

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The interconversion of active and inactive corticosteroids – cortisol and cortisone, respectively, in humans – is modulated by isozymes of 11β-hydroxysteroid dehydrogenase (11-HSD). Studies of this process have provided crucial insights into glucocorticoid effects in a wide variety of tissues. The 11-HSD1 isozyme functions mainly as an oxoreductase (cortisone to cortisol) and is expressed at high levels in the liver and other glucocorticoid target tissues. Because it is required for full physiological effects of cortisol, it has emerged as a drug target for metabolic syndrome and type 2 diabetes. Mutations in the corresponding HSD11B1 gene, or in the H6PD gene encoding hexose-6-phosphate dehydrogenase (which supplies the NADPH required for the oxoreductase activity of 11-HSD1), cause apparent cortisone reductase deficiency, a rare syndrome of adrenocortical hyperactivity and hyperandrogenism. In contrast, the 11-HSD2 isozyme functions as a dehydrogenase (cortisol to cortisone) and is expressed mainly in mineralocorticoid target tissues, where it bars access of cortisol to the mineralocorticoid receptor. Mutations in the HSD11B2 gene encoding 11-HSD2 cause the syndrome of apparent mineralocorticoid excess, a severe form of familial hypertension. The role of this enzyme in the pathogenesis of common forms of low-renin hypertension remains uncertain.

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

Abstract: 11β-HSD1 may be an important enzyme in the pathogenesis of fatty liver and visceral obesity and a promising target for their treatment.

Cited by 21 publications

References 41 publications

Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice

Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice

Interaction of HSD11B1 and H6PD polymorphisms in subjects with type 2 diabetes are protective factors against obesity: a cross-sectional study

Alterations of Cortisol Metabolism in Human Disorders

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