Pathophysiologic mechanisms leading to intrahepatic fat accumulation in obese youth

项目摘要 非酒精性脂肪性肝病（NAFLD）是儿科最常见的肝病， 30%的肥胖青年术语NAFLD定义了广泛的疾病严重程度，从简单的 无肝损伤（脂肪变性）的肝内脂肪蓄积至非酒精性脂肪性肝炎（NASH）、纤维化和 肝硬化一项为期20年的回顾性研究表明，在青年时期患NAFLD的受试者 终末期肝病的死亡率比年龄和性别相似的健康受试者高出约13倍 NAFLD在西班牙裔青年中非常普遍，而非西班牙裔黑人（NHB）青年则受到保护， 即使在严重肥胖和胰岛素抵抗的情况下，肝内脂肪积累也是如此。了解 这些差异背后的病理生理学可能揭示导致NAFLD的机制， 肥胖青年我们的初步数据表明，西班牙裔和NHB肥胖青年可能有不同的能力， 通过糖酵解代谢碳水化合物（CHO），西班牙裔显示出比NHB更高的糖酵解。 因此，西班牙裔患者可能会经历更高等级的三环酸循环（TCA）和肝脏新发 脂肪生成（DNL）。在本研究中，我们的目标是解决以下问题1）是不同的 西班牙裔和NHB在发展NAFLD中的易感性，因为西班牙裔的能力更高， 通过糖酵解、TCA循环和DNL代谢CHO？2)这些代谢变化是否预示着 西班牙裔年轻人的疾病吗3)糖酵解、TCA和DNL的较高速率是否由高水平驱动，而不是- 葡萄糖水平随时间的病理变化？为了实现我们的目标，我们计划招募30名西班牙裔和30名 NHB肥胖青年和测量糖酵解通过使用一种新的方法来评估乳酸动力学， 用~（13）C-丙酸盐和D_2O测定TCA循环和DNL。此外，我们将评估糖酵解 在基线时，每12年对150名无脂肪肝的西班牙裔肥胖青年的肝内脂肪含量进行一次 2个月，以确定较高的糖酵解速率是否先于肝内脂肪积累。到 评估糖酵解中的代谢变化是否由较高但非病理性的葡萄糖水平驱动，我们将 通过使用连续葡萄糖监测系统，每六个月测量十天的葡萄糖变化。如果 这些研究的成功将为儿童NAFLD的发病机制提供新的见解， 测试新治疗方法的途径。

Project Summary Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease in pediatrics, affecting about 30% of obese youth. The term NAFLD defines a wide spectrum of disease severity ranging from simple intrahepatic fat accumulation without liver injury (steatosis) to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. A 20-year retrospective study has shown that subjects who develop NAFLD during their youth have about 13 times higher mortality rate for end-stage liver disease than healthy subjects of similar age and gender NAFLD is highly prevalent among Hispanic youth, while non-Hispanic Black (NHB) youth are protected against intrahepatic fat accumulation even in the presence of severe obesity and insulin resistance. Understanding the pathophysiology underlying these differences could shed new light on the mechanisms leading to NAFLD in obese youth. Our preliminary data suggest that Hispanic and NHB obese youth might have a different ability to metabolize carbohydrates (CHO) through glycolysis, with Hispanics showing higher glycolysis than NHB. Therefore, Hispanics might experience a higher rated tricyclic acid cycle (TCA) and hepatic de novo lipogenesis (DNL). In the present study we aim to address the following questions 1) Is the different susceptibility between Hispanics and NHB in developing NAFLD due to a higher capability of Hispanics to metabolize CHO through glycolysis, TCA cycle and DNL? 2) Do these metabolic changes anticipate the onset of the disease in Hispanic youth? 3) Are the higher rates of glycolysis, TCA and DNL driven by high but not- pathologic changes in glucose levels over time? To address our aims we plan to recruit 30 Hispanics and 30 NHB obese youth and to measure glycolysis by using a new method to assess lactate kinetics and to determine the TCA cycle and DNL by using 13C-Propionate and D2O. Moreover, we will assess glycolysis and intrahepatic fat content in a group of 150 Hispanic obese youth without fatty liver at baseline every 12 months for two years to determine whether higher glycolytic rates precede intrahepatic fat accumulation. To assess whether metabolic changes in glycolysis are driven by higher but not-pathologic glucose levels, we will measure glucose changes over ten days every six months by using a continuous glucose monitoring system. If successful these studies will provide novel insight into the pathogenesis of pediatric NAFLD and will open new avenues to test novel therapeutic approaches.