Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism

Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline- and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J ~ C57BL/6J ~ C3H/HeJ < 129S1/SvImJ ~ CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor alpha (PPARalpha)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPARapha-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice. Male A/J, C3H/HeJ and WSB/EiJ inbred mice were maintained on either control or choline- and folate-deficient (CFD) diets for 12 weeks. Gene expression profiles in the livers from control mice and mice fed a CFD-diet were investigated.非酒精性脂肪性肝病（Nonalcoholic fatty liver disease, NAFLD）是美国及发达国家的重大健康问题与慢性肝病的首要致病原因。在人类群体中，遗传因素可显著影响个体对NAFLD的易感性。本研究的核心目标为：比较不同近交系小鼠在甲基供体缺乏诱导的肝损伤严重程度上的个体间差异幅度，并探究该差异背后的潜在调控机制。 给小鼠饲喂胆碱与叶酸缺乏饮食12周，可诱发与NAFLD病理特征相似的肝损伤。不同品系小鼠的肝损伤程度存在显著差异，其敏感性排序为：A/J ~ C57BL/6J ~ C3H/HeJ < 129S1/SvImJ ~ CAST/EiJ < PWK/PhJ < WSB/EiJ。 NAFLD相关肝损伤严重程度的品系间差异，与脂代谢相关基因的调控紊乱高度相关，主要体现为过氧化物酶体增殖物激活受体α（peroxisome proliferator receptor alpha, PPARα）所调控的脂质分解代谢通路基因的下调表达。肝脏组织中氧化应激及氧化应激诱导的DNA损伤标志物水平亦出现升高，但该指标与肝损伤严重程度并无显著相关性。 上述研究结果表明，PPARα调控的代谢网络是决定小鼠品系间NAFLD易感性与肝损伤严重程度的关键机制之一。本研究将雄性A/J、C3H/HeJ及WSB/EiJ近交小鼠分别饲喂对照饮食或胆碱叶酸缺乏（choline- and folate-deficient, CFD）饮食12周，进而探究对照小鼠与CFD饮食饲喂小鼠肝脏组织的基因表达谱特征。