NONALCOHOLIC STEATOHEPATITIS (NASH): IS LEPTIN AN ETIOLOGICAL FACTOR (PHASE2)

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 众所周知，非酒精性脂肪性肝炎(或NASH)是由脂肪沉积在肝脏中并因脂肪沉积而形成疤痕而引起的。这种情况更常发生在超重和肥胖的人身上。它通常与胰岛素激素的作用抵抗有关，胰岛素激素是调节体内血糖的主要激素。脂肪细胞分泌一种叫做瘦素的荷尔蒙。近年来，我们了解到肥胖或超重的人会产生过多的瘦素。血液中的瘦素过多可能会导致胰岛素抵抗。矛盾的是，没有任何脂肪细胞的患者也存在胰岛素抵抗。在这些患者中，胰岛素抵抗是由于缺乏瘦素造成的，瘦素替代显著改善了胰岛素抵抗和肝脏中的脂肪沉积。在早期的一项研究中，我们测定了非酒精性脂肪性肝炎患者的瘦素水平，以及这些水平与体脂水平以及对胰岛素的反应性之间的关系。我们发现，与体脂含量相比，NASH患者的一部分患者的瘦素水平相对较低。我们现在想看看将瘦素水平恢复到正常水平是否会改善这些患者的疾病过程。我们现在将研究那些瘦素水平较低的患者。我们的研究患者将是年龄在18岁到65岁(含)之间的男性患者，他们的肝脏疾病没有任何其他原因。我们已经对身体尺寸进行了一些限制，以便将从正常体重到肥胖范围的一系列患者包括在内。他们还将显示瘦素水平较低(仅相当于正常人群的25%)。我们将使用安进公司生产的基因工程形式的瘦素。瘦素将通过皮下注射给药。我们计划继续治疗一年，并通过肝脏活检来评估肝脏疾病的变化。我们还将遵循我们在被称为第一阶段的早期研究中研究的代谢参数(例如血液胆固醇、肝功能、胰岛素抵抗)和身体组成特征(例如体内脂肪分布模式)。我们预计，当血液瘦素水平恢复正常时，低血瘦素水平的患者将显示出他们的肝病和胰岛素抵抗的改善。 ‘

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nonalcoholic steatohepatitis (or NASH) is known to be caused by deposition of fat in the liver and development of scarring as a consequence of fat deposition. This condition occurs more frequently in overweight and obese persons. It is often associated with resistance to the actions of insulin hormone, the primary hormone regulating blood sugar in the body. Fat cells secrete a hormone called leptin. In recent years, we have learned that obese or overweight persons make too much leptin. Having too much leptin in the blood may contribute to insulin resistance. Paradoxically, patients who do not have any fat cells also have insulin resistance. In these patients, the resistance to the actions of insulin is caused by the absence of leptin and leptin replacement significantly improves insulin resistance and fat deposition in the liver. In an earlier study, we determined the leptin levels in patients with nonalcoholic steatohepatitis and how these levels are related to body fat levels as well as responsiveness to insulin. We saw that a subgroup of patients with NASH have relatively low levels of leptin in contrast to the amount of body fat they had. We now would like to see if restoring leptin levels to normal will improve the disease process in these patients. We will now study those patients in whom we have seen low levels of leptin. Our study patients will be male patients, aged between 18 and 65 (inclusive), who do not have any other cause for their liver disease. We have put some restrictions in body size such that a spectrum of patients from normal weight to obese range would be included. They will also demonstrate low leptin levels (levels similar to only 25 % of normal population). We will use genetically engineered form of leptin manufactured by Amgen Inc. Leptin will be given via injections under the skin. We plan to continue therapy for a period of one year and evaluate the change in liver disease by a liver biopsy. We will also follow the metabolic parameters (e.g. blood cholesterol, liver function, insulin resistance) and body composition characteristics (e.g. the pattern of fat distribution in the body) that we studied in our earlier study which we called Phase 1. We expect that patients with low blood leptin levels will show improvement in their liver disease and insulin resistance when their blood leptin levels are restored to normal. '