Department of Pediatrics, Digestive Diseases and Nutrition Center, The State University of New York, Buffalo, NY 14214, USA.
Metabolism. 2011 Jul;60(7):1001-11. doi: 10.1016/j.metabol.2010.10.003. Epub 2010 Nov 13.
Fatty liver is a prerequisite for the development of nonalcoholic steatohepatitis (NASH). The homeostasis of hepatic lipid is determined by the dynamic balance of multiple pathways introducing lipids into or removing lipids from hepatocytes. We aim to study the different contributions of major lipid pathways to fat deposition in NASH livers. Expression of the lipid metabolism-related genes was analyzed by microarray and quantitative real-time polymerase chain reaction analysis. The expression levels of genes responsible for the rate-limiting steps of fatty acid uptake (CD36, FABPpm, SLC27A2, and SLC27A5), de novo synthesis (ACACB), oxidation (CPT-1), and very low-density lipoprotein (VLDL) secretion (ApoB) were used to evaluate the relative activity of each pathway. The expression levels for CD36 and CPT-1 were confirmed by Western blot analysis. Fatty acid uptake pathways were up-regulated to a higher degree than other pathways. The de novo synthesis pathway was also up-regulated more than both VLDL secretion and fatty acid oxidation pathways. In contrast to other NASH livers, one NASH liver exhibited lower ApoB and CPT-1 expression levels than normal controls. The increased fatty acid uptake and de novo synthesis were the most common causes for steatosis in NASH patients. In a rare case, impaired VLDL secretion and fatty acid oxidation contributed to the development of steatosis. Our study promises a simple method for the determination of why hepatic steatosis occurs in individual patients. This method may allow specific targeting of therapeutic treatments in individual patients.
脂肪肝是非酒精性脂肪性肝炎（NASH）发展的前提。肝内脂质的动态平衡由将脂质引入或从肝细胞中去除脂质的多种途径的动态平衡决定。我们旨在研究主要脂质途径对 NASH 肝脏脂肪沉积的不同贡献。通过微阵列和定量实时聚合酶链反应分析分析脂质代谢相关基因的表达。脂肪酸摄取（CD36、FABPpm、SLC27A2 和 SLC27A5）、从头合成（ACACB）、氧化（CPT-1）和极低密度脂蛋白（VLDL）分泌（ApoB）的限速步骤负责的基因的表达水平用于评估每个途径的相对活性。通过 Western blot 分析确认了 CD36 和 CPT-1 的表达水平。脂肪酸摄取途径的上调程度高于其他途径。从头合成途径的上调程度也高于 VLDL 分泌和脂肪酸氧化途径。与其他 NASH 肝脏相比，一个 NASH 肝脏的 ApoB 和 CPT-1 表达水平低于正常对照。增加的脂肪酸摄取和从头合成是 NASH 患者脂肪变性的最常见原因。在一种罕见的情况下，VLDL 分泌和脂肪酸氧化受损导致脂肪变性的发展。我们的研究为确定为什么个体患者会发生肝脂肪变性提供了一种简单的方法。这种方法可以允许针对个体患者的特定治疗方法。
