De novo lipogenesis in the pathogenesis of non-alcoholic fatty liver disease

描述（由申请人提供）：脂肪肝-脂肪变性-影响约三分之一的人口。它的患病率正在上升，似乎与全球肥胖和2型糖尿病的增长同步。脂肪变性和导致非酒精性脂肪性肝病的机制尚不清楚。我们认为碳水化合物（CHO）到脂质的肝脏转化（de novo lipogenesis， DNL）是肝脏脂肪积累和伴随的血脂异常的关键因素，通过饮食抑制DNL将减少肝脏脂肪并改善脂肪变性患者的代谢谱。这些假设是基于我们和其他人已经确定的研究，肝脏DNL的分数可以根据受试者的饮食和/或健康状况而显著变化；特别是，饮食中的果糖是一种强有力的脂肪生成刺激物。在本提案中，我们将进行基于临床研究中心（CRC）的研究，比较脂肪变性和匹配的非脂肪变性对照中DNL和VLDL的动力学率，并评估它们与脂质特征的关系（目的1）。习惯性摄入果糖和其他单糖超过总能量摄入15%的脂肪变性个体将被随机分配至两种低脂饮食中的一种，仅CHO类型不同，以确定饮食诱导的DNL变化是否会影响肝脏脂肪通量和含量（目的2）。我们假设，富含复合CHO的饮食比含有典型数量的简单CHO（包括果糖）的饮食更能减少DNL和肝脏脂肪。这项饮食干预研究包括为期6周的25%能量限制门诊阶段，以促进中度体重减轻和改善胰岛素敏感性，随后是为期一周的体重维持，最后5天作为住院治疗，在此期间，所有在基线进行的研究（目标1）将重复进行。最先进的稳定同位素技术将用于评估空腹和进食条件下肝脏DNL、apoB100周转、VLDL-TG通量和脂肪分解。肝脏脂肪将通过质子磁共振波谱测量。这些研究将使我们能够评估DNL作为调节肝脏脂肪含量和通量的机制的重要性，以及CHO质量在脂肪变性患者饮食指导中的意义。

DESCRIPTION (provided by applicant): Fatty liver - steatosis - affects about one third of the population. Its prevalence is rising and seems to parallel the global increase in obesity and type-2 diabetes. The mechanisms underlying steatosis and leading to non-alcoholic fatty liver disease are poorly understood. We propose that the hepatic conversion of carbohydrates (CHO) to lipids (de novo lipogenesis, DNL) is a key factor in the accumulation of excess liver fat and the accompanying dyslipidemia and that suppressing DNL by diet will reduce liver fat and improve the metabolic profile in patients with steatosis. These hypotheses are based on studies in which we and others have established that fractional hepatic DNL can vary dramatically depending on the diet and/or health status of a subject; and, in particular, that dietary fructose is a potent lipogenic stimulus. In this proposal we will perform Clinical Research Center (CRC) based studies to compare the rates of DNL and VLDL kinetics in steatotic and matched non-steatotic controls and evaluate their relationship to lipid profiles (Aim 1). The steatotic individuals whose habitual intake of fructose and other simple sugars exceeds 15% of total energy intake will then be randomized to consume one of two low-fat diets that differ only in CHO type to determine whether diet-induced changes in DNL affect liver fat flux, content (Aim 2). We hypothesize that a diet that is rich in complex CHO will achieve greater decreases in DNL and liver fat than one that contains typical amounts of simple CHO, including fructose. This dietary intervention study includes a 6-week 25% energy restriction outpatient phase to promote moderate weight loss and improve insulin sensitivity, followed by a week weight maintenance with the last 5 days as an inpatient stay during which all of the studies performed at baseline (Aim 1) will be repeated. State-of-the-art stable isotope techniques will be used to assess hepatic DNL, apoB100 turnover, VLDL-TG fluxes, and lipolysis under fasting and fed conditions. Liver fat will be measured by proton magnetic resonance spectroscopy. These studies will allow us to evaluate the importance of DNL as a mechanism modulating liver fat content and flux, and the significance of CHO quality in dietary guidance for steatotic patients.