Glucocorticoid metabolism and the control of metabolic phenotype.

糖皮质激素代谢和代谢表型的控制。

• 批准号: G0802765/1
• 负责人: Jeremy Tomlinson
• 金额: $ 184.09万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0802765%2F1
• 关键词: Glucocorticoid; metabolism; control; metabolic; phenotype.

Obesity is associated with medical complications that include heart attacks, strokes, type 2 diabetes and the development of fatty liver disease which can progress to liver failure. The mechanisms that contribute to fat deposition within the liver are not fully understood and we believe that increased local production and / or decreased breakdown of the steroid hormone, cortisol, may contribute to the disease. In addition, cortisol acting on fat within the abdomen may fuel fatty liver disease by increasing delivery of fat precursors to the liver. Importantly, patients who either produce too much cortisol or who are prescribed large doses of steroid hormones develop many of these complications including obesity and fatty liver disease.We will use cells cultured from liver and fat to determine the effect of cortisol on fat accumulation. We will also assess the impact of modifying production and break down of cortisol. We will create rodent models in which we have genetically manipulated the enzymes that produce and breakdown cortisol. We believe that decreasing cortisol production and enhancing breakdown will have beneficial effects. Finally, we will conduct clinical studies using drugs that decrease cortisol production to see if they can decrease fat accumulation within the liver.

肥胖与医学并发症有关，包括心脏病发作，中风，2型糖尿病和脂肪肝疾病的发展，脂肪肝疾病可能发展为肝功能衰竭。导致肝脏内脂肪沉积的机制尚不完全清楚，我们认为类固醇激素皮质醇的局部产生增加和/或分解减少可能导致该疾病。此外，作用于腹部脂肪的皮质醇可能会通过增加脂肪前体向肝脏的输送而加剧脂肪肝疾病。重要的是，产生过多皮质醇或服用大剂量类固醇激素的患者会出现许多并发症，包括肥胖和脂肪肝。我们将使用从肝脏和脂肪中培养的细胞来确定皮质醇对脂肪积累的影响。我们还将评估修改皮质醇的产生和分解的影响。我们将建立啮齿动物模型，在这些模型中，我们对产生和分解皮质醇的酶进行了基因操作。我们相信，减少皮质醇的产生和促进分解将产生有益的影响。最后，我们将使用减少皮质醇产生的药物进行临床研究，看看它们是否可以减少肝脏内的脂肪积累。