OBESITY AND NONALCOHOLIC FATTY LIVER DISEASE

描述(申请人提供)：肥胖是非酒精性脂肪性肝病(NAFLD)的主要风险因素，NAFLD代表一系列肝脏疾病，组织学特征为脂肪变性、脂肪性肝炎、纤维化和肝硬变。非酒精性脂肪肝在美国是一个主要的健康问题，因为它的高患病率以及与严重的肝脏异常的因果关系。然而，肥胖者发生非酒精性脂肪肝的机制(S)以及非酒精性脂肪肝本身对肝脏代谢功能的影响尚不清楚。这种知识上的差距使人们很难确定有效的治疗方法。虽然减肥通常被推荐给患有NAFLD的肥胖患者，但现有的数据表明，快速而显著的减肥会增加炎症，甚至肝功能衰竭。这项建议的主要目的是为了更好地了解：1)肥胖者NAFLD的发病机制和病理生理学，以及2)显著减肥对与NAFLD相关的组织学和代谢异常的影响。我们将检验下列假设：1)肥胖导致肝脏脂肪堆积，由于脂肪组织过度释放脂肪酸和FFA利用率增加，2)肝脏脂肪含量增加导致肝脏产生胰岛素抵抗葡萄糖，并改变肝脂蛋白和蛋白质的合成，3)肝脏脂肪含量增加导致脂质过氧化和肝脏氧化应激增加，肝脏炎症、坏死和纤维化，以及4)一旦患者体重稳定，显著减肥可改善NAFLD的组织和代谢特征。将执行两项研究方案。在方案1中，30名I类肥胖(BMI 30-34.9 kg/m2)和NAFLD的受试者将被随机分为低碳水化合物、高脂肪饮食(以增加脂肪分解和血浆FFA利用率)、NIASPAN治疗(以减少脂肪分解和血浆FFA利用率)或观察(对照)6周。另外10名肝脂含量正常的肥胖者也将接受低碳水化合物、高脂肪饮食治疗，以确定过量的FFA是否也会增加肝脏正常者的肝脏脂肪。在方案2中，II级和III级肥胖(BMI 35-50 kg/m2)的受试者将接受胃旁路手术。干预前后将进行下列代谢评估：1)评估基础血糖和脂肪酸动力学，2)评估高胰岛素-正常血糖钳夹手术期间肝脏、脂肪组织、肌肉和胰岛素的敏感性，3)肝脂蛋白代谢(VLDL-TG和VLDL-载脂蛋白B分泌)，4)肝脏蛋白质(白蛋白和纤维蛋白原)合成，4)磁共振波谱评估肝脏脂肪含量(仅在方案1受试者中)，以及5)肝脏脂质过氧化和纤维化通过免疫组织化学检测。这些研究的结果将为开发新的治疗肥胖症患者NAFLD的干预措施奠定基础。

DESCRIPTION (provided by applicant): Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD), which represents a spectrum of liver diseases characterized histologically as steatosis, steatohepatitis, fibrosis and cirrhosis. NAFLD is a major health problem in the U.S. because of its high prevalence and causal relationship with serious liver abnormalities. However, the mechanism(s) responsible for developing NAFLD in obese persons and the effects of NAFLD itself on hepatic metabolic function are not known. This gap in knowledge has made it difficult to identify effective therapy. Although weight loss is generally recommended for obese patients with NAFLD, the available data suggest that rapid and marked weight loss increases inflammation, and even liver failure. The primary goal of this proposal is to provide a better understanding of: 1) the pathogenesis and pathophysiology of NAFLD in obese persons, and 2) the effect of marked weight loss on the histologic and metabolic abnormalities associated with NAFLD. We will test the following hypotheses: 1) obesity causes hepatic fat accumulation, because of excessive fatty acid release from adipose tissue and increased FFA availability, 2) increased hepatic fat content causes insulin-resistant glucose production by the liver and altered hepatic lipoprotein and protein synthesis, 3) increased hepatic fat content causes increases lipid peroxidation and hepatic oxidative stress, hepatic inflammation, necrosis and fibrosis, and 4) marked weight loss improves the histological and metabolic features of NAFLD once patients are weight stable. Two study protocols will be performed. In Protocol 1, 30 subjects with class I obesity (BMI 30-34.9 kg/m 2) and NAFLD will be randomized to 6 weeks of a low-carbohydrate, high-fat diet (to increase lipolysis and plasma FFA availability), niaspan therapy (to decrease lipolysis and plasma FFA availability), or observation (control). An additional 10 obese subjects with normal hepatic lipid content will also be treated with a low-carbohydrate, high-fat diet to determine whether excess FFA availability also increases hepatic fat in persons with normal liver. In Protocol 2, subjects with class II and III obesity (BMI 35-50 kg/m 2) will undergo gastric bypass surgery. The following metabolic evaluations will be performed before and after the interventions: 1) assessment of basal glucose and fatty acid kinetics, 2) assessment of liver, adipose tissue, muscle and insulin sensitivity during a hyperinsulinemic-euglycemic clamp procedure, 3) hepatic lipoprotein metabolism (VLDL-TG and VLDL-apolipoprotein B secretion), 4) hepatic protein (albumin, and fibrinogen) synthesis, 4) assessment of hepatic fat content by magnetic resonance spectroscopy (in Protocol 1 subjects only), and 5) liver lipid peroxidation and fibrogenesis by using immunohistochemistry. The results from these studies will lay the groundwork for the development of novel therapeutic interventions for NAFLD in obese patients.