Is the metabolic syndrome an intracellular Cushing state? Effects of multiple humoral factors on the transcriptional activity of the hepatic glucocorticoid-activating enzyme (11beta-hydroxysteroid dehydrogenase type 1) gene.
Although glucocorticoid, as "gluco-" literally implies, plays an important role in maintaining the blood glucose level, excess of glucocorticoid production/action is known to cause impaired glucose tolerance and diabetes. Since 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which converts inactive cortisone to active cortisol, is primarily expressed in the liver, an enhanced expression of the enzyme may increase the intracellular glucocorticoid level and thus increase the hepatic glucose production. In this study, we examined the effects of multiple humoral factors related to the metabolic syndrome on the transcriptional activity of 11beta-HSD1 gene in hepatocytes in vitro. We found that, among the factors examined, adipocyte-derived cytokines (adipokines), like TNFalpha and IL-1beta, potently stimulated the transcriptional activity of 11beta-HSD1 gene in human HuH7 cells. In contrast, only minimal effects of other humoral factors were observed when they were used alone. Interestingly, however, when applied in combination, they synergistically enhanced the transcriptional activity of 11beta-HSD1 gene. They also potentiated the effects of cytokines. Glucocorticoid receptor (GR)-dependent transcription was indeed increased even with an inactive glucocorticoid cortisone following TNFalpha pretreatment, indicating the enhanced intracellular conversion. Finally, PPARgamma/PPARalpha agonists, clinically used as anti-diabetic drugs, significantly inhibited the transcriptional activity of 11beta-HSD1. Altogether, our data strongly suggest that combination of the humoral factors related to the metabolic syndrome, including the adipokines, synergistically enhances the hepatic expression of 11beta-HSD1 gene and causes the intracellular Cushing state in the liver by increasing the intracellular glucocorticoid level. We assume that the observed synergistic effects of these factors on 11beta-HSD1 may, at least partly, explain the reason whereby accumulation of the multiple risk factors facilitates the derangement of glucose and lipid metabolism in the metabolic syndrome.
Iwasaki
Yasumasa
Y
Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan. iwasaki@kochi-u.ac.jp
Takayasu
Shinobu
S
Nishiyama
Mitsuru
M
Tsugita
Makoto
M
Taguchi
Takafumi
T
Asai
Masato
M
Yoshida
Masanori
M
Kambayashi
Machiko
M
Hashimoto
Kozo
K
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D002839:Chromans / Q000378:metabolism; D002994:Clofibrate / Q000378:metabolism; D003348:Cortisone / Q000378:metabolism; D003480:Cushing Syndrome / Q000097:blood* / Q000201:enzymology* / Q000503:physiopathology; D003907:Dexamethasone / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D024821:Metabolic Syndrome / Q000097:blood* / Q000201:enzymology* / Q000503:physiopathology; D008687:Metformin / Q000378:metabolism; D008969:Molecular Sequence Data; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000924:Anticholesteremic Agents; D002839:Chromans; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin; D053583:Interleukin-1beta; D011965:Receptors, Glucocorticoid; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D008687:Metformin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D002994:Clofibrate; D000077288:Troglitazone; D003348:Cortisone; D006854:Hydrocortisone