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

我们目前正处于包括肥胖和2型糖尿病在内的代谢性疾病的全球流行之中。这些情况通常与肝脏脂肪沉积有关，即所谓的非酒精性脂肪性肝病（NAFLD）。NAFLD是一种疾病谱系，从简单的脂肪积累到炎症（非酒精性脂肪性肝炎，NASH），可发展为纤维化和瘢痕形成，最终导致肝硬化，可能需要肝移植。此外，它还会显著增加患原发性肝癌（肝细胞癌，HCC）的风险。在5年内，这将成为肝移植最常见的原因。这种情况还会增加心脏病发作和中风的风险，以及与肝脏直接相关的问题。目前还没有特定的治疗方法被批准用于治疗NAFLD，诊断病情分期和严重程度的金标准测试（肝活检）与显著并发症相关。作为该提案的一部分，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无需肝活检就能诊断和分期疾病严重程度的替代方法。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。我们提出这一建议的数据表明，我们可以非常有效地诊断NAFLD谱的最极端端，这有助于确定一种特定的类固醇代谢酶（AKR1D1），我们认为它在NAFLD的进展和发展中至关重要。我们已经建立了一个缺失AKR1D1的小鼠模型，雌性小鼠不会因为高脂肪饮食而体重增加，并且不会患糖尿病。在本提案中，我们将进一步表征这些动物的代谢，通过观察食物消耗、能量消耗，以及使用不同的饮食方案来复制NAFLD的所有阶段，以观察它们是否被保护免受NAFLD和HCC的发展。最后，我们还将开始开发AKR1D1特异性抑制剂的药物，看看这些药物将来是否可能代表NAFLD和代谢性肝病的潜在治疗方法。

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.