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

脂肪肝的病理生理学：了解炎症、胰岛素抵抗和铁过载

• 批准号: RGPIN-2015-04224
• 负责人: RouvinenWatt, Kirsti
• 金额: $ 1.75万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=589665
• 关键词: Pathophysiology; fatty; liver; disease; Understanding

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.

脂肪肝正在迅速成为家畜、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发展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从根本上改变，其特点是高热量食物丰富，体力活动有限。在肉食性水貂中，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。它与过度喂养和身体脂肪积累，蛋白质-热量营养不良，为繁殖做准备而急剧减肥，食欲不振，以及快速动员身体脂肪储备用于产奶有关;所有营养不平衡的状态。我的目标是了解脂肪肝疾病的潜在生物学以及炎症在胰岛素抵抗和肝脏内过量铁积累发展中的作用。我计划在水貂身上研究肝脏脂肪积累导致氧化应激、肝脏炎症和铁超负荷疾病的生理机制。动物研究将使我们能够了解脂肪肝疾病和相关代谢综合征的器官，组织和整个动物水平的表现。为了了解细胞水平的机制，我将使用肝细胞和巨噬细胞培养来研究胰岛素抵抗和铁储存的发展，预防和逆转。为了研究这些反应，我将使用临床化学，组织学，生物化学和分子方法。我将通过定量实时聚合酶链反应、蛋白质印迹法和酶谱法评估与肝脏炎症早期阶段相关的基因表达和蛋白质的量和活性。了解基本的病理生理机制将是至关重要的，在预防和逆转这种往往致命的疾病和相关的健康和福利成本。更好的代谢健康反过来又会改善生长和免疫功能，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。鉴于肝脏在体内脂肪、血糖和铁代谢中的核心作用，以及代谢综合征在全球迅速增加的患病率，这项研究将对家畜和人类健康具有重要的应用价值。