Iwasaki Yasumasa, Takayasu Shinobu, Nishiyama Mitsuru, Tsugita Makoto, Taguchi Takafumi, Asai Masato, Yoshida Masanori, Kambayashi Machiko, Hashimoto Kozo
Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan.
Mol Cell Endocrinol. 2008 Mar 26;285(1-2):10-8. doi: 10.1016/j.mce.2008.01.012. Epub 2008 Feb 2.
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.
虽然糖皮质激素，正如其“葡糖-”字面意思所暗示的，在维持血糖水平方面发挥着重要作用，但已知糖皮质激素产生/作用过量会导致糖耐量受损和糖尿病。由于将无活性的可的松转化为活性皮质醇的11β-羟基类固醇脱氢酶1型（11β-HSD1）主要在肝脏中表达，该酶表达增强可能会增加细胞内糖皮质激素水平，从而增加肝脏葡萄糖生成。在本研究中，我们在体外检测了与代谢综合征相关的多种体液因子对肝细胞中11β-HSD1基因转录活性的影响。我们发现，在所检测的因子中，脂肪细胞衍生的细胞因子（脂肪因子），如肿瘤坏死因子α（TNFα）和白细胞介素-1β（IL-1β），能有效刺激人HuH7细胞中11β-HSD1基因的转录活性。相比之下，其他体液因子单独使用时仅观察到最小的作用。然而，有趣的是，当联合应用时，它们会协同增强11β-HSD1基因的转录活性。它们还增强了细胞因子的作用。即使在TNFα预处理后使用无活性的糖皮质激素可的松，糖皮质激素受体（GR）依赖性转录确实增加，这表明细胞内转化增强。最后，临床上用作抗糖尿病药物的过氧化物酶体增殖物激活受体γ（PPARγ）/过氧化物酶体增殖物激活受体α（PPARα）激动剂显著抑制了11β-HSD1的转录活性。总之，我们的数据强烈表明，与代谢综合征相关的体液因子，包括脂肪因子的组合，通过增加细胞内糖皮质激素水平，协同增强肝脏中11β-HSD1基因的表达，并导致肝脏细胞内库欣状态。我们推测，这些因子对11β-HSD1的协同作用可能至少部分解释了多种危险因素的积累促进代谢综合征中葡萄糖和脂质代谢紊乱的原因。
