Limits...
Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.

Lavery GG, Zielinska AE, Gathercole LL, Hughes B, Semjonous N, Guest P, Saqib K, Sherlock M, Reynolds G, Morgan SA, Tomlinson JW, Walker EA, Rabbitt EH, Stewart PM - Endocrinology (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. g.g.lavery@bham.ac.uk

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.

Show MeSH

Related in: MedlinePlus

Hepatic triglyceride accumulation and gene expression. A, Representative H&E staining depicts pathology associated with hepatic steatosis, which was similar between control and LKO sections (by light microscope at ×40 magnification). Graph shows liver triglyceride content on low-fat (LF) and high-fat (HF) diet in control and LKO mice (*, P < 0.05 vs. LF diet). B, Relative lipogenic gene mRNA levels in control and LKO mice on HF diet (*, P < 0.05 vs. control). C, Relative expression of mRNA for genes associated sensitive to GC, cholesterol metabolism, and β-oxidation. D, Representative H&E and Oil Red O staining of 16-h-fasted control and LKO livers showing similar levels of steatosis (by light microscope at ×40 magnification). SREBP1c, Sterol regulatory element-binding protein 1c; FAS, fatty acid synthase; ACC1, acetyl-CoA carboxylase 1; ACC2, acetyl-CoA carboxylase 2; SCD1, stearoyl-coenzyme A desaturase 1; ELOVL6, elongation of long-chain fatty acids family member 6; H6PDH, hexose-6-phospahte dehydrogenase; AGT, angiotensinogen; FGA, fibrinogen alpha; LDLr, low density lipoprotein receptor; HMG, 3-hydroxy-3-methyl-glutaryl-CoA reductase; LIPC, hepatic lipase; PPARa, peroxisome proliferator-activated receptor alpha; CPT1a, carnitine palmitoyltransferase 1a; Con, control; GC, glucocorticoid related genes; Chol, cholesterol metabolism related genes; Beta-Ox, beta oxidation related genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3475725&req=5

Figure 5: Hepatic triglyceride accumulation and gene expression. A, Representative H&E staining depicts pathology associated with hepatic steatosis, which was similar between control and LKO sections (by light microscope at ×40 magnification). Graph shows liver triglyceride content on low-fat (LF) and high-fat (HF) diet in control and LKO mice (*, P < 0.05 vs. LF diet). B, Relative lipogenic gene mRNA levels in control and LKO mice on HF diet (*, P < 0.05 vs. control). C, Relative expression of mRNA for genes associated sensitive to GC, cholesterol metabolism, and β-oxidation. D, Representative H&E and Oil Red O staining of 16-h-fasted control and LKO livers showing similar levels of steatosis (by light microscope at ×40 magnification). SREBP1c, Sterol regulatory element-binding protein 1c; FAS, fatty acid synthase; ACC1, acetyl-CoA carboxylase 1; ACC2, acetyl-CoA carboxylase 2; SCD1, stearoyl-coenzyme A desaturase 1; ELOVL6, elongation of long-chain fatty acids family member 6; H6PDH, hexose-6-phospahte dehydrogenase; AGT, angiotensinogen; FGA, fibrinogen alpha; LDLr, low density lipoprotein receptor; HMG, 3-hydroxy-3-methyl-glutaryl-CoA reductase; LIPC, hepatic lipase; PPARa, peroxisome proliferator-activated receptor alpha; CPT1a, carnitine palmitoyltransferase 1a; Con, control; GC, glucocorticoid related genes; Chol, cholesterol metabolism related genes; Beta-Ox, beta oxidation related genes.

Mentions: Staining of liver with hematoxylin and eosin (H&E) and Oil Red O shows no difference in hepatic fat content in LKO mice on either diet. A high-fat diet did induced pathology associated with steatosis equally in both LKO and control livers (Fig. 5A). Biochemical analyses confirmed that although the high-fat diet greatly increased hepatic triglyceride content, it was to a similar degree in both LKO and control mice (Fig. 5A), indicating that LKO mice have no protection from steatosis.


Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.

Lavery GG, Zielinska AE, Gathercole LL, Hughes B, Semjonous N, Guest P, Saqib K, Sherlock M, Reynolds G, Morgan SA, Tomlinson JW, Walker EA, Rabbitt EH, Stewart PM - Endocrinology (2012)

Hepatic triglyceride accumulation and gene expression. A, Representative H&E staining depicts pathology associated with hepatic steatosis, which was similar between control and LKO sections (by light microscope at ×40 magnification). Graph shows liver triglyceride content on low-fat (LF) and high-fat (HF) diet in control and LKO mice (*, P < 0.05 vs. LF diet). B, Relative lipogenic gene mRNA levels in control and LKO mice on HF diet (*, P < 0.05 vs. control). C, Relative expression of mRNA for genes associated sensitive to GC, cholesterol metabolism, and β-oxidation. D, Representative H&E and Oil Red O staining of 16-h-fasted control and LKO livers showing similar levels of steatosis (by light microscope at ×40 magnification). SREBP1c, Sterol regulatory element-binding protein 1c; FAS, fatty acid synthase; ACC1, acetyl-CoA carboxylase 1; ACC2, acetyl-CoA carboxylase 2; SCD1, stearoyl-coenzyme A desaturase 1; ELOVL6, elongation of long-chain fatty acids family member 6; H6PDH, hexose-6-phospahte dehydrogenase; AGT, angiotensinogen; FGA, fibrinogen alpha; LDLr, low density lipoprotein receptor; HMG, 3-hydroxy-3-methyl-glutaryl-CoA reductase; LIPC, hepatic lipase; PPARa, peroxisome proliferator-activated receptor alpha; CPT1a, carnitine palmitoyltransferase 1a; Con, control; GC, glucocorticoid related genes; Chol, cholesterol metabolism related genes; Beta-Ox, beta oxidation related genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475725&req=5

Figure 5: Hepatic triglyceride accumulation and gene expression. A, Representative H&E staining depicts pathology associated with hepatic steatosis, which was similar between control and LKO sections (by light microscope at ×40 magnification). Graph shows liver triglyceride content on low-fat (LF) and high-fat (HF) diet in control and LKO mice (*, P < 0.05 vs. LF diet). B, Relative lipogenic gene mRNA levels in control and LKO mice on HF diet (*, P < 0.05 vs. control). C, Relative expression of mRNA for genes associated sensitive to GC, cholesterol metabolism, and β-oxidation. D, Representative H&E and Oil Red O staining of 16-h-fasted control and LKO livers showing similar levels of steatosis (by light microscope at ×40 magnification). SREBP1c, Sterol regulatory element-binding protein 1c; FAS, fatty acid synthase; ACC1, acetyl-CoA carboxylase 1; ACC2, acetyl-CoA carboxylase 2; SCD1, stearoyl-coenzyme A desaturase 1; ELOVL6, elongation of long-chain fatty acids family member 6; H6PDH, hexose-6-phospahte dehydrogenase; AGT, angiotensinogen; FGA, fibrinogen alpha; LDLr, low density lipoprotein receptor; HMG, 3-hydroxy-3-methyl-glutaryl-CoA reductase; LIPC, hepatic lipase; PPARa, peroxisome proliferator-activated receptor alpha; CPT1a, carnitine palmitoyltransferase 1a; Con, control; GC, glucocorticoid related genes; Chol, cholesterol metabolism related genes; Beta-Ox, beta oxidation related genes.
Mentions: Staining of liver with hematoxylin and eosin (H&E) and Oil Red O shows no difference in hepatic fat content in LKO mice on either diet. A high-fat diet did induced pathology associated with steatosis equally in both LKO and control livers (Fig. 5A). Biochemical analyses confirmed that although the high-fat diet greatly increased hepatic triglyceride content, it was to a similar degree in both LKO and control mice (Fig. 5A), indicating that LKO mice have no protection from steatosis.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. g.g.lavery@bham.ac.uk

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.

Show MeSH
Related in: MedlinePlus