Pathophysiology of fatty liver disease: Understanding inflammation, insulin resistance and iron-overload

脂肪肝正迅速成为家畜、圈养野生动物和人类的严重健康问题。它是与肥胖和胰岛素抵抗相关的代谢综合征的一个关键特征。圈养家畜的生活方式已经发生了根本性的变化，其特点是大量的高热量食物和有限的体力活动。在食肉水貂中，脂肪肝发展非常迅速，没有症状，经常导致死亡，造成重大的经济和遗传损失。它与过度喂养和体脂积累、蛋白质热量营养不良、为准备繁殖而急剧瘦身、食欲不振以及为产奶而迅速调动体脂储备有关；都是营养不平衡的状态。我的目标是了解脂肪性肝病的潜在生物学，以及炎症在胰岛素抵抗和肝脏内过度铁积累发展中的作用。我计划在水貂身上研究肝脏脂肪堆积导致氧化应激、肝脏炎症和铁超载疾病的生理机制。动物研究将使我们了解脂肪性肝病及相关代谢综合征的器官、组织和全动物水平的表现。为了了解细胞水平的机制，我将通过肝细胞和巨噬细胞培养来研究胰岛素抵抗和铁储存的发生、预防和逆转。为了研究这些反应，我将使用临床化学、组织学、生化和分子方法。我将通过实时定量聚合酶链反应、Western blotting和酶谱分析来评估基因表达以及与肝脏炎症早期阶段相关的蛋白质的数量和活性。了解基本的病理生理机制对于预防和逆转这种通常致命的疾病以及相关的健康和福利成本至关重要。更好的代谢健康反过来会导致更好的生长和免疫功能，以及最佳的繁殖性能，这些都是家畜生产和濒危物种保护计划的重要标准。鉴于肝脏在体脂、血糖和铁代谢中的核心作用，以及全球代谢综合征患病率的迅速增加，这项研究将对家畜和人类健康具有重要的应用价值。

Fatty liver disease is rapidly becoming a serious health concern in domestic animals, captive wildlife and humans. It is a key feature in the metabolic syndrome associated with obesity and the development of insulin resistance. The lifestyle of domestic livestock has been fundamentally changed in captivity, to one that is characterized by abundance of high calorie food and limited physical activity. In the carnivorous mink, fatty liver develops very rapidly, is without symptoms, and often results in death causing significant economic and genetic losses. It is associated with excessive feeding and body fat accumulation, protein-calorie malnutrition, drastic slimming in preparation for breeding, lack of appetite, and rapid mobilization of body fat reserves for milk production; all states of nutritional imbalance. My goal is to understand the underlying biology of fatty liver disease and the role of inflammation in the development of insulin resistance and excessive iron accumulation within the liver. I plan to study in mink, the physiological mechanisms by which liver fat accumulation leads to oxidative stress, liver inflammation, and iron-overload disease. The animal studies will enable us to learn about the organ, tissue and whole animal level manifestations of fatty liver disease and the associated metabolic syndrome. In order to understand the cellular level mechanisms, I will investigate the development, prevention and reversal of insulin resistance and iron storage using liver cell and macrophage cell culture. To study these responses, I will use clinical-chemical, histological, biochemical and molecular methods. I will assess the gene expression and the amount and activity of proteins associated with the early stages of liver inflammation by quantitative real-time polymerase chain reaction, Western blotting and zymography. Understanding the fundamental pathophysiological mechanisms will be critical in the prevention and reversal of this often fatal disease and the associated health and welfare costs. Better metabolic health will in turn result in improved growth and immune function, and optimum reproductive performance, all significant criteria in domestic animal production and endangered species conservation programs. Given the liver’s central role in body fat, blood sugar and iron metabolism and the rapidly increasing global prevalence of the metabolic syndrome this research will have vital application to both domestic animal and human health.