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。它的流行率正在上升，似乎与全球肥胖和2型糖尿病的增加平行。脂肪变性和导致非酒精性脂肪肝的机制知之甚少。我们认为，肝脏碳水化合物（CHO）转化为脂质（从头脂肪生成，DNL）是过量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特征。这些假设是基于我们和其他人已经确定的研究，即肝DNL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，饮食果糖是一种有效的脂肪生成刺激。在本提案中，我们将进行基于临床研究中心（CRC）的研究，以比较脂肪变性和匹配的非脂肪变性对照中DNL和VLDL动力学的发生率，并评价其与血脂谱的关系（目标1）。果糖和其他单糖的习惯性摄入量超过总能量摄入量15%的脂肪变性个体将被随机分配到两种低脂饮食中的一种，这两种饮食仅在CHO类型上不同，以确定饮食诱导的DNL变化是否影响肝脏脂肪流量，含量（目标2）。我们假设，富含复杂CHO的饮食将比含有典型量的简单CHO（包括果糖）的饮食更大程度地降低DNL和肝脏脂肪。这项饮食干预研究包括6周的25%能量限制门诊阶段，以促进中度体重减轻并改善胰岛素敏感性，随后是一周的体重维持，最后5天作为住院治疗，在此期间将重复在基线（目标1）进行的所有研究。将使用最先进的稳定同位素技术评估空腹和进食条件下的肝脏DNL、apoB 100转换、VLDL-TG通量和脂解。将通过质子磁共振波谱法测量肝脏脂肪。这些研究将使我们能够评估DNL作为调节肝脏脂肪含量和流量的机制的重要性，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.