Lack of Significant Metabolic Abnormalities in Mice with Liver-Specific Disruption of 11β-Hydroxysteroid Dehydrogenase Type 1

Abstract

Glucocorticoids (GC) are implicated in the development of metabolic syndrome, and patients with GC excess share many clinical features, such as central obesity and glucose intolerance. In patients with obesity or type 2 diabetes, systemic GC concentrations seem to be invariably normal. Tissue GC concentrations determined by the hypothalamic-pituitary-adrenal (HPA) axis and local cortisol (corticosterone in mice) regeneration from cortisone (11-dehydrocorticosterone in mice) by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, principally expressed in the liver. Transgenic mice have demonstrated the importance of 11β-HSD1 in mediating aspects of the metabolic syndrome, as well as HPA axis control. In order to address the primacy of hepatic 11β-HSD1 in regulating metabolism and the HPA axis, we have generated liver-specific 11β-HSD1 knockout (LKO) mice, assessed biomarkers of GC metabolism, and examined responses to high-fat feeding. LKO mice were able to regenerate cortisol from cortisone to 40% of control and had no discernible difference in a urinary metabolite marker of 11β-HSD1 activity. Although circulating corticosterone was unaltered, adrenal size was increased, indicative of chronic HPA stimulation. There was a mild improvement in glucose tolerance but with insulin sensitivity largely unaffected. Adiposity and body weight were unaffected as were aspects of hepatic lipid homeostasis, triglyceride accumulation, and serum lipids. Additionally, no changes in the expression of genes involved in glucose or lipid homeostasis were observed. Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile. These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies. The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.

Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma

“…However, this discrepancy might be attributable to a compensatory production of corticosterone by other tissues and a downregulation of 11b- HSD2 by the liver. In fact, the authors detected around 40% cortisol levels in knockout mice relative to control mice after cortisone challenge 40 . In addition, Dex has been reported to render non-haematological cancer cells more resistant to antitumour drugs [41][42][43][44] .…”

“…Therefore, our findings suggest that the downregulation of 11b-HSD1 and upregulation of 11b-HSD2 might generate a profound effect on gluconeogenesis in malignant hepatocytes via regulating GC activities. Recently, Lavery et al 40 found that hepatic PEPCK and G6Pase were expressed in the liver-specific 11b-HSD1 knockout mice, implicating that the loss of 11b-HSD1 does not have a profound effect on gluconeogenesis. However, this discrepancy might be attributable to a compensatory production of corticosterone by other tissues and a downregulation of 11b- HSD2 by the liver.…”

11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

“…All procedures were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986. Six-week-old male global (GKO) (C57BL/6) (31), liver-specific (LKO) (C57BL/6J/129SvJ) (19), and adipose-specific (FKO) C57BL/6J (SI Text) 11β-HSD1 KO mice, with WT controls, had ad libitum access to standard chow and drinking water supplemented with either CORT (100 μg/mL, 0.66% ethanol), 11DHC (100 μg/mL, 0.66% ethanol), or vehicle (0.66% ethanol) for 5 wk. Treatments were replaced twice weekly.…”

“…Details with respect to the generation of these transgenic lines are presented in ref. 19, SI Text, and Fig. S6 A-E.…”

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

“…Genetic knockdown of 11b-HSD1 (69) as well as pharmacological inhibition (70) decreases hepatic steatosis. Interestingly, this may not reflect changes in hepatic GC availability as liver-specific 11b-HSD1 deletion does not impact significantly on metabolic phenotype and this may point to a more crucial role of GC metabolism within adipose tissue (71). The role of the A-ring reductases has been less well explored, although there is some evidence to suggest that deletion of 5aR type 1 increases the risk of development of hepatic steatosis (72).…”