Dissecting the steroid metabolome in the pathogenesis and treatment of metabolic liver disease

剖析类固醇代谢组在代谢性肝病发病机制和治疗中的作用

• 批准号: MR/P011462/1
• 负责人: Jeremy Tomlinson
• 金额: $ 187.63万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP011462%2F1
• 关键词: Dissecting; steroid; metabolome; pathogenesis; treatment

We are currently in the midst of a global epidemic of metabolic disease that includes obesity and type 2 diabetes. These conditions are frequently associated with fat deposition in the liver, so-called non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of disease that extends from simple fat accumulation through to inflammation (non-alcoholic steatohepatitis, NASH) which can progress to fibrosis and scarring and eventually lead to cirrhosis of the liver which may require a liver transplant. In addition, it significantly increases your risk of developing primary liver cancer (hepatocellular cancer, HCC). Within 5 years, this will become the commonest cause of liver transplantation. The condition is also associated with an increased risk of heart attacks and strokes as well as problems directly related to the liver. There are currently no specific treatments that are licenced for the treatment of NAFLD and the gold-standard test to diagnose the stage and severity of the condition (liver biopsy) is associated with significant complications. As part of this proposal, we will measure natural steroid hormone metabolites in urine samples from patients with NAFLD (as identified on liver biopsy) as well as HCC to see if this can provide an alternative way to diagnose and stage the severity of the disease without the need for a liver biopsy. This approach will be compared against standard blood tests as well as scans including magnetic resonance imaging. The data that we have generated leading up to this proposal have suggested that we can very effectively diagnose the most extreme ends of the NAFLD spectrum and this has helped to identify one specific steroid metabolizing enzyme (AKR1D1) that we believe to be crucial in the progression and development of NAFLD. We have already generated a mouse model with deletion of AKR1D1 and the female mice do not put on weight with a high fat diet and are protected from diabetes. Within this proposal we will further characterize the metabolism of these animals looking at food consumption, energy expenditure as well as using different dietary regimens to replicate all the stages of NAFLD to see if they are protected from the development of NAFLD and HCC. Finally, we will also begin to develop drugs that are specific inhibitors of AKR1D1 to see if these may represent potential treatments for NAFLD and metabolic liver disease in the future.

我们目前正处于全球流行的代谢性疾病，包括肥胖和2型糖尿病。这些疾病通常与肝脏中的脂肪沉积有关，即所谓的非酒精性脂肪性肝病（NAFLD）。NAFLD是一系列疾病，从简单的脂肪积累延伸到炎症（非酒精性脂肪性肝炎，NASH），炎症可进展为纤维化和瘢痕形成，最终导致可能需要肝移植的肝硬化。此外，它会显着增加患原发性肝癌（肝细胞癌，HCC）的风险。在5年内，这将成为肝移植的最常见原因。这种情况也与心脏病发作和中风的风险增加以及与肝脏直接相关的问题有关。目前没有特定的治疗方法被许可用于治疗NAFLD，诊断病情阶段和严重程度的金标准测试（肝活检）与严重并发症相关。作为本提案的一部分，我们将测量NAFLD（通过肝活检确定）和HCC患者尿液样本中的天然类固醇激素代谢物，看看这是否可以提供一种诊断和分期疾病严重程度的替代方法，而无需进行肝活检。这种方法将与标准血液测试以及包括磁共振成像在内的扫描进行比较。我们产生的导致这一提议的数据表明，我们可以非常有效地诊断NAFLD谱的最极端，这有助于确定一种特定的类固醇代谢酶（AKR1D1），我们认为这在NAFLD的进展和发展中至关重要。我们已经建立了一个AKR1D1缺失的小鼠模型，雌性小鼠不会因高脂肪饮食而增加体重，并且不会患糖尿病。在本提案中，我们将进一步描述这些动物的代谢特征，观察食物消耗、能量消耗以及使用不同的饮食方案来复制NAFLD的所有阶段，看看它们是否受到保护，免受NAFLD和HCC的发展。最后，我们还将开始开发AKR1D1特异性抑制剂药物，看看这些药物是否可能代表未来NAFLD和代谢性肝病的潜在治疗方法。

项目成果

A novel model for predicting diabetes remission after bariatric surgery based on the measurement of C-peptide and creatinine in serum: A pilot study

基于血清中 C 肽和肌酐测量的预测减肥手术后糖尿病缓解的新模型：一项试点研究

• DOI: 10.1016/j.numecd.2023.12.008
• 发表时间: 2023
• 期刊: Nutrition, Metabolism and Cardiovascular Diseases
• 作者: Colosimo S

Bile acids as drivers and biomarkers of hepatocellular carcinoma.

• DOI: 10.4254/wjh.v14.i9.1730
• 发表时间: 2022-09-27
• 期刊: World journal of hepatology
• 影响因子: 2.4
• 作者: Colosimo S;Tomlinson JW
• 通讯作者: Tomlinson JW

Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial.

• DOI: 10.1186/s12902-018-0315-6
• 发表时间: 2018-11-26
• 期刊: BMC endocrine disorders
• 影响因子: 2.7
• 作者: Baig S;Veeranna V;Bolton S;Edwards N;Tomlinson JW;Manolopoulos K;Moran J;Steeds RP;Geberhiwot T
• 通讯作者: Geberhiwot T

Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism

• DOI: 10.1172/jci.insight.93136
• 发表时间: 2017-04-20
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Arlt, Wiebke;Lang, Katharina;Reincke, Martin
• 通讯作者: Reincke, Martin