11β-羟基类固醇脱氢酶1型在代谢综合征中的作用
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摘要
MS是一组以糖脂代谢异常、中心性肥胖、高血压和高尿酸为特征的系列症候群,与心血管事件和糖尿病发生密切相关。11β-羟基类固醇脱氢酶1型(11β-HSD1)作为一个新的MS靶点受到关注。11β-HSD1参与皮质醇与皮质酮的转化,其基因敲除可改善肥胖、高脂血症和高血糖。11β-HSD1抑制剂可减轻IR,但其应用受到相关不良反应限制。
MS,which is highly related tothe occurrence of cardiovascular disease and T2 DM,is characterized by glucose and fat metabolic dysregulation,central obesity,hypertension and hyperuricemia.11β-hydroxysteroid dehydrogenase type 1(11β-HSD1)is regarded as a new therapeutic target for MS.11β-HSD1 converts inactive glucocorticoid to active glucocorticoid.11β-HSD1 knockout improves obesity,hyperlipidemia andhyperglycemia.The inhibition of 11β-HSD1 alleviates IR in human and rodents,but the application of 11β-HSD1 inhibitors is limited by the side effects.
MS,which is highly related tothe occurrence of cardiovascular disease and T2 DM,is characterized by glucose and fat metabolic dysregulation,central obesity,hypertension and hyperuricemia.11β-hydroxysteroid dehydrogenase type 1(11β-HSD1)is regarded as a new therapeutic target for MS.11β-HSD1 converts inactive glucocorticoid to active glucocorticoid.11β-HSD1 knockout improves obesity,hyperlipidemia andhyperglycemia.The inhibition of 11β-HSD1 alleviates IR in human and rodents,but the application of 11β-HSD1 inhibitors is limited by the side effects.
引文
[1]Gathercole LL,Lavery GG,Morgan SA,et al.11beta-hydroxysteroid dehydrogenase 1:translational and therapeutic aspects.Endocr Rev,2013,34:525-555.
[2]Edwards CR,Stewart PM,Burt D,et al.Localisation of 11betahydroxysteroid dehydrogenase——tissue specific protector of the mineralocorticoid receptor.Lancet,1988,2:986-989.
[3]Kannisto K,Pietilainen KH,Ehrenborg E,et al.Overexpression of 11beta-hydroxysteroid dehydrogenase-1in adipose tissue is associated with acquired obesity and features of insulin resistance:studies in young adult monozygotic twins.J Clin Endocrinol Metab,2004,89:4414-4421.
[4]Olza J,Gil-Campos M,Leis R,et al.A gene variant of 11betahydroxysteroid dehydrogenase type 1is associated with obesity in children.Int J Obes(Lond),2012,36:1558-1563.
[5]Livingstone DE,Grassick SL,Currie GL,et al.Dysregulation of glucocorticoid metabolism in murine obesity:comparable effects of leptin resistance and deficiency.J Endocrinol,2009,201:211-218.
[6]Seckl JR,Morton NM,Chapman KE,et al.Glucocorticoids and11beta-hydroxysteroid dehydrogenase in adipose tissue.Recent Prog Horm Res,2004,59:359-393.
[7]Paterson JM,Morton NM,Fievet C,et al.Metabolic syndrome without obesity:Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1in transgenic mice.Proc Natl Acad Sci U S A,2004,101:7088-7093.
[8]Masuzaki H,Paterson J,Shinyama H,et al.A transgenic model of visceral obesity and the metabolic syndrome.Science,2001,294:2166-2170.
[9]Kotelevtsev Y,Holmes MC,Burchell A,et al.11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.Proc Natl Acad Sci U S A,1997,94:14924-14929.
[10]Morton NM,Holmes MC,Fievet C,et al.Improved lipid and lipoprotein profile,hepatic insulin sensitivity,and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice.J Bio Chem,2001,276:41293-41300.
[11]Lavery GG,Zielinska AE,Gathercole LL,et al.Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11beta-hydroxysteroid dehydrogenase type 1.Endocrinology,2012,153:3236-3248.
[12]Nuotio-Antar AM,Hachey DL,Hasty AH,et al.Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese,hyperlipidemic mice.Am J Physiol Endocrinol Metab,2007,293:E1517-E1528.
[13]Walker BR,Connacher AA,Lindsay RM,et al.Carbenoxolone increases hepatic insulin sensitivity in man:a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation.J Clin Endocrinol Metab,1995,80:3155-3159.
[14]Andrews RC,Rooyackers O,Walker BR.Effects of the 11betahydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2diabetes.J Clin Endocrinol Metab,2003,88:285-291.
[15]Anagnostis P,Katsiki N,Adamidou F,et al.11beta-Hydroxysteroid dehydrogenase type 1inhibitors:novel agents for the treatment of metabolic syndrome and obesity-related disorders?Metabolism,2013,62:21-33.
[16]Park JS,Rhee SD,Kang NS,et al.Anti-diabetic and anti-adipogenic effects of a novel selective 11beta-hydroxysteroid dehydrogenase type 1inhibitor,2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone(KR-66344).Biochem Pharmacol,2011,81:1028-1035.
[17]Li G,Hernandez-Ono A,Crooke RM,et al.Antisense reduction of 11beta-hydroxysteroid dehydrogenase type 1enhances energy expenditure and insulin sensitivity independent of food intake in C57BL/6J mice on a western-type diet.Metabolism,2012,61:823-835.
[18]Rosenstock J,Banarer S,Fonseca VA,et al.The 11-beta-hydroxysteroid dehydrogenase type 1inhibitor INCB13739improves hyperglycemia in patients with type 2diabetes inadequately controlled by metformin monotherapy.Diabetes Care,2010,33:1516-1522.
[19]Stefan N,Ramsauer M,Jordan P,et al.Inhibition of 11β-HSD1with RO5093151for non-alcoholic fatty liver disease:a multicentre,randomised,double-blind,placebo-controlled trial.Lancet Diabetes Endocrinol,2014,2:406-416.
[20]Shah S,Hermanowski-Vosatka A,Gibson K,et al.Efficacy and safety of the selective 11beta-HSD-1inhibitors MK-0736and MK-0916in overweight and obese patients with hypertension.J Am Soc Hypertens,2011,5:166-176.
[21]Feig PU,Shah S,Hermanowski-Vosatka A,et al.Effects of an11beta-hydroxysteroid dehydrogenase type 1inhibitor,MK-0916,in patients with type 2diabetes mellitus and metabolic syndrome.Diabetes Obes Metab,2011,13:498-504.
[22]Courtney R,Stewart PM,Toh M,et al.Modulation of 11betahydroxysteroid dehydrogenase(11beta HSD)activity biomarkers and pharmacokinetics of PF-00915275,a selective 11beta HSD1inhibitor.J Clin Endocrinol Metab,2008,93:550-556.
[2]Edwards CR,Stewart PM,Burt D,et al.Localisation of 11betahydroxysteroid dehydrogenase——tissue specific protector of the mineralocorticoid receptor.Lancet,1988,2:986-989.
[3]Kannisto K,Pietilainen KH,Ehrenborg E,et al.Overexpression of 11beta-hydroxysteroid dehydrogenase-1in adipose tissue is associated with acquired obesity and features of insulin resistance:studies in young adult monozygotic twins.J Clin Endocrinol Metab,2004,89:4414-4421.
[4]Olza J,Gil-Campos M,Leis R,et al.A gene variant of 11betahydroxysteroid dehydrogenase type 1is associated with obesity in children.Int J Obes(Lond),2012,36:1558-1563.
[5]Livingstone DE,Grassick SL,Currie GL,et al.Dysregulation of glucocorticoid metabolism in murine obesity:comparable effects of leptin resistance and deficiency.J Endocrinol,2009,201:211-218.
[6]Seckl JR,Morton NM,Chapman KE,et al.Glucocorticoids and11beta-hydroxysteroid dehydrogenase in adipose tissue.Recent Prog Horm Res,2004,59:359-393.
[7]Paterson JM,Morton NM,Fievet C,et al.Metabolic syndrome without obesity:Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1in transgenic mice.Proc Natl Acad Sci U S A,2004,101:7088-7093.
[8]Masuzaki H,Paterson J,Shinyama H,et al.A transgenic model of visceral obesity and the metabolic syndrome.Science,2001,294:2166-2170.
[9]Kotelevtsev Y,Holmes MC,Burchell A,et al.11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.Proc Natl Acad Sci U S A,1997,94:14924-14929.
[10]Morton NM,Holmes MC,Fievet C,et al.Improved lipid and lipoprotein profile,hepatic insulin sensitivity,and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice.J Bio Chem,2001,276:41293-41300.
[11]Lavery GG,Zielinska AE,Gathercole LL,et al.Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11beta-hydroxysteroid dehydrogenase type 1.Endocrinology,2012,153:3236-3248.
[12]Nuotio-Antar AM,Hachey DL,Hasty AH,et al.Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese,hyperlipidemic mice.Am J Physiol Endocrinol Metab,2007,293:E1517-E1528.
[13]Walker BR,Connacher AA,Lindsay RM,et al.Carbenoxolone increases hepatic insulin sensitivity in man:a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation.J Clin Endocrinol Metab,1995,80:3155-3159.
[14]Andrews RC,Rooyackers O,Walker BR.Effects of the 11betahydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2diabetes.J Clin Endocrinol Metab,2003,88:285-291.
[15]Anagnostis P,Katsiki N,Adamidou F,et al.11beta-Hydroxysteroid dehydrogenase type 1inhibitors:novel agents for the treatment of metabolic syndrome and obesity-related disorders?Metabolism,2013,62:21-33.
[16]Park JS,Rhee SD,Kang NS,et al.Anti-diabetic and anti-adipogenic effects of a novel selective 11beta-hydroxysteroid dehydrogenase type 1inhibitor,2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone(KR-66344).Biochem Pharmacol,2011,81:1028-1035.
[17]Li G,Hernandez-Ono A,Crooke RM,et al.Antisense reduction of 11beta-hydroxysteroid dehydrogenase type 1enhances energy expenditure and insulin sensitivity independent of food intake in C57BL/6J mice on a western-type diet.Metabolism,2012,61:823-835.
[18]Rosenstock J,Banarer S,Fonseca VA,et al.The 11-beta-hydroxysteroid dehydrogenase type 1inhibitor INCB13739improves hyperglycemia in patients with type 2diabetes inadequately controlled by metformin monotherapy.Diabetes Care,2010,33:1516-1522.
[19]Stefan N,Ramsauer M,Jordan P,et al.Inhibition of 11β-HSD1with RO5093151for non-alcoholic fatty liver disease:a multicentre,randomised,double-blind,placebo-controlled trial.Lancet Diabetes Endocrinol,2014,2:406-416.
[20]Shah S,Hermanowski-Vosatka A,Gibson K,et al.Efficacy and safety of the selective 11beta-HSD-1inhibitors MK-0736and MK-0916in overweight and obese patients with hypertension.J Am Soc Hypertens,2011,5:166-176.
[21]Feig PU,Shah S,Hermanowski-Vosatka A,et al.Effects of an11beta-hydroxysteroid dehydrogenase type 1inhibitor,MK-0916,in patients with type 2diabetes mellitus and metabolic syndrome.Diabetes Obes Metab,2011,13:498-504.
[22]Courtney R,Stewart PM,Toh M,et al.Modulation of 11betahydroxysteroid dehydrogenase(11beta HSD)activity biomarkers and pharmacokinetics of PF-00915275,a selective 11beta HSD1inhibitor.J Clin Endocrinol Metab,2008,93:550-556.