非酒精性脂肪性肝炎的啮齿动物营养模型：物种、品系和性别差异研究
Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies.
作者信息
Kirsch Richard, Clarkson Vivian, Shephard Enid G, Marais David A, Jaffer Mohamed A, Woodburne Vivienne E, Kirsch Ralph E, Hall Pauline de la M
机构信息
Department of Anatomical Pathology, University of Cape Town, Cape Town, Western Cape, South Africa.
出版信息
J Gastroenterol Hepatol. 2003 Nov;18(11):1272-82. doi: 10.1046/j.1440-1746.2003.03198.x.
BACKGROUND AND AIM
The methionine choline-deficient (MCD) diet leads to steatohepatitis in rodents. The aim of the present study was to investigate species, strain and sex differences in this nutritional model of non-alcoholic steatohepatitis (NASH).
METHODS
Male and female Wistar, Long-Evans and Sprague-Dawley rats, and C57/BL6 mice (n = 6 per group) were fed a MCD diet for 4 weeks. Control groups received an identical diet supplemented with choline bitartrate (0.2% w/w) and methionine (0.3% w/w). Liver pathology (steatosis and inflammation) and ultrastructure, liver lipid profile (total lipids, triglycerides, lipid peroxidation products), liver : body mass ratios and serum alanine aminotransferase (ALT) levels were compared between these groups.
RESULTS
The MCD diet-fed male rats developed greater steatosis (P < 0.001), had higher liver lipid content (P < 0.05) and had higher serum ALT levels (P < 0.005) than did female rats. Wistar rats (both sexes) had higher liver lipid levels (P < 0.05), serum ALT levels (P < 0.05), and liver mass : body mass ratios (P < 0.025) than did Long-Evans and Sprague-Dawley rats. In female groups, Wistar rats showed greater fatty change than did the other two strains (P < 0.05). All rats fed the MCD diet developed hepatic steatosis, but necrosis and inflammation were minor features and fibrosis was absent. Compared with Wistar rats, male C57/BL6 mice showed a marked increase in inflammatory foci (P < 0.001), end products of lipid peroxidation (free thiobarbituric acid reactive substances) (P < 0.005), and mitochondrial injury, while showing less steatosis (P < 0.005), lower hepatic triglyceride levels, (P < 0.005) and lower early lipid peroxidation products (conjugated dienes and lipid hydroperoxides; P < 0.005 and P < 0.01, respectively).
CONCLUSIONS
The Wistar strain and the male sex are associated with the greatest degree of steatosis in rats subjected to the MCD diet. Of the groups studied, male C57/BL6 mice develop the most inflammation and necrosis, lipid peroxidation, and ultrastructural injury, and best approximate the histological features of NASH.
背景与目的
蛋氨酸胆碱缺乏（MCD）饮食可导致啮齿动物发生脂肪性肝炎。本研究旨在探讨非酒精性脂肪性肝炎（NASH）这一营养模型中的物种、品系和性别差异。
方法
将雄性和雌性Wistar大鼠、Long-Evans大鼠、Sprague-Dawley大鼠以及C57/BL6小鼠（每组n = 6）喂养MCD饮食4周。对照组给予补充了酒石酸胆碱（0.2% w/w）和蛋氨酸（0.3% w/w）的相同饮食。比较这些组之间的肝脏病理学（脂肪变性和炎症）及超微结构、肝脏脂质谱（总脂质、甘油三酯、脂质过氧化产物）、肝脏与体重比值以及血清丙氨酸氨基转移酶（ALT）水平。
结果
与雌性大鼠相比，喂养MCD饮食的雄性大鼠发生了更严重的脂肪变性（P < 0.001），肝脏脂质含量更高（P < 0.05），血清ALT水平更高（P < 0.005）。Wistar大鼠（雌雄两性）的肝脏脂质水平（P < 0.05）、血清ALT水平（P < 0.05）以及肝脏重量与体重比值（P < 0.025）均高于Long-Evans大鼠和Sprague-Dawley大鼠。在雌性组中，Wistar大鼠的脂肪变化比其他两个品系更明显（P < 0.05）。所有喂养MCD饮食的大鼠均发生了肝脏脂肪变性，但坏死和炎症较轻，且无纤维化。与Wistar大鼠相比，雄性C57/BL6小鼠的炎症灶显著增加（P < 0.001）、脂质过氧化终产物（游离硫代巴比妥酸反应性物质）增加（P < 0.005）以及线粒体损伤增加，同时脂肪变性较轻（P < 0.005）、肝脏甘油三酯水平较低（P < 0.005）以及早期脂质过氧化产物较低（共轭二烯和氢过氧化物脂质；分别为P < 0.005和P < 0.01）。
结论
Wistar品系和雄性与接受MCD饮食的大鼠中最严重程度的脂肪变性相关。在所研究的组中，雄性C57/BL6小鼠发生的炎症、坏死、脂质过氧化和超微结构损伤最为严重，最接近NASH的组织学特征。
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