Leikin-Frenkel Alicia, Goldiner Ilana, Leikin-Gobbi Diana, Rosenberg Ruth, Bonen Hamutal, Litvak Alex, Bernheim Joelle, Konikoff Fred M, Gilat Tuvia
Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver, Tel-Aviv University, Tel-Aviv, Israel.
Eur J Gastroenterol Hepatol. 2008 Dec;20(12):1205-13. doi: 10.1097/MEG.0b013e3282fc9743.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in industrialized countries. It has no accepted medical therapy. Fatty acid-bile acid conjugates (FABACs) were proven to prevent diet-induced NAFLD in rodents.
This study was undertaken to test whether oral FABACs are also effective in reducing liver fat in preestablished diet-induced NAFLD.
NAFLD was induced in mice and rats by a high-fat diet and maintained by various proportions thereof. The FABACs used were conjugates of cholic acid with either arachidic or stearic acids.
FABAC therapy reduced liver fat in all four series of experiments. The rapidity of the effect was inversely proportional to the concentration of fat in the maintenance diet. In mice on a 25% maintenance diet FABACs decreased total liver lipids by about 30% in 4 weeks (P<0.03). Diglycerides (P<0.003) and triglycerides (P<0.01) were the main neutral liver lipids that decreased during FABAC therapy. Both FABACs tested reduced liver fat in NAFLD at doses of 25 and 150 mg/kg/day. High-fat diet increased, whereas FABAC therapy decreased plasma 16 : 1/(16 : 0+16 : 1) fatty acid ratio - a marker of stearoyl CoA desaturase activity. In HepG2 cells FABACs decreased de-novo fatty acid synthesis dose dependently.
Oral FABAC therapy decreased liver fat in preestablished NAFLD in mice and rats. Inhibition of stearoyl CoA desaturase activity and fatty acid synthesis are mechanisms that may contribute to this decrease. FABACs may be potential therapeutic agents for human NAFLD.
非酒精性脂肪性肝病（NAFLD）是工业化国家最常见的慢性肝病。目前尚无公认的药物治疗方法。脂肪酸-胆汁酸共轭物（FABACs）已被证明可预防啮齿动物因饮食诱导的NAFLD。
本研究旨在测试口服FABACs对已形成的饮食诱导性NAFLD患者肝脏脂肪减少是否也有效。
通过高脂饮食在小鼠和大鼠中诱导NAFLD，并通过不同比例的高脂饮食维持。所用的FABACs是胆酸与花生酸或硬脂酸的共轭物。
在所有四个系列的实验中，FABAC治疗均降低了肝脏脂肪。效果的快速程度与维持饮食中的脂肪浓度成反比。在维持饮食为25%的小鼠中，FABACs在4周内使肝脏总脂质减少约30%（P<0.03）。甘油二酯（P<0.003）和甘油三酯（P<0.01）是FABAC治疗期间减少的主要中性肝脏脂质。两种测试的FABACs在25和150mg/kg/天的剂量下均可降低NAFLD患者的肝脏脂肪。高脂饮食会升高，而FABAC治疗会降低血浆16:1/(16:0 + 16:1)脂肪酸比值——这是硬脂酰辅酶A去饱和酶活性的标志物。在HepG2细胞中，FABACs剂量依赖性地降低了从头脂肪酸合成。
口服FABAC治疗可降低已形成NAFLD的小鼠和大鼠的肝脏脂肪。抑制硬脂酰辅酶A去饱和酶活性和脂肪酸合成可能是导致这种减少的机制。FABACs可能是人类NAFLD的潜在治疗药物。
