Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high-fat diet in the genetically diverse Collaborative Cross mouse model.
Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high-fat diet in the genetically diverse Collaborative Cross mouse model.
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DOI：
10.1096/fj.202000194r
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发表时间：
2020-06
期刊：
影响因子：
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通讯作者：
Pogribny IP
中科院分区：
文献类型：
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作者：
de Conti A;Tryndyak V;Willett RA;Borowa-Mazgaj B;Watson A;Patton R;Khare S;Muskhelishvili L;Olson GR;Avigan MI;Cerniglia CE;Ross SA;Sanyal AJ;Beland FA;Rusyn I;Pogribny IP
非酒精性脂肪性肝病（NAFLD）发展中的个体间变异性和性二态性仍然知之甚少。在本研究中，雄性和雌性品系的协作杂交（CC）小鼠喂食高脂肪和高蔗糖（HF/HS）饮食或对照饮食12周，以研究NAFLD发展中的个体间和性别特异性变化。肝脏脂肪变性的严重程度在性别和个体菌株之间存在差异，并伴有胰岛素抵抗血清标志物的升高，包括总胆固醇、低密度脂蛋白、高密度脂蛋白、磷脂和葡萄糖的增加。NAFLD的发生与雄性和雌性小鼠中关键脂肪酸摄取和从头脂肪生成基因Pparg、Mogat 1、Cd 36、Mogab 1、Fabp 2和Gdf 15的过度表达有关。Pparg、Mogat 1和Cd 36的表达与雄性小鼠的肝脏甘油三酯呈正相关，而Mogat 1和Cd 36的表达与雌性小鼠的肝脏甘油三酯呈正相关。我们的研究结果表明，CC小鼠与HF/HS饮食诱导的改变相结合的价值，作为一种方法来研究非酒精性脂肪肝和早期非酒精性脂肪性肝炎发病机制的易感性和个体间变异性，在人口水平上，发现易感和耐药队列，并确定疾病易感性的性别特异性分子决定因素。
The interindividual variability and sexual dimorphisms in the development of nonalcoholic fatty liver disease (NAFLD) are still poorly understood. In the present study, male and female strains of Collaborative Cross (CC) mice were fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks to investigate interindividual and sex-specific variations in the development of NAFLD. The severity of liver steatosis varied between sexes and individual strains and was accompanied by an elevation of serum markers of insulin resistance, including increases in total cholesterol, low-density lipoproteins, high-density lipoproteins, phospholipids, and glucose. The development of NAFLD was associated with over-expression of critical fatty acid uptake and de novo lipogenesis genes Pparg, Mogat1, Cd36, Acaab1, Fabp2, and Gdf15 in male and female mice. The expression of Pparg, Mogat1, and Cd36 was positively correlated with liver triglycerides in male mice, and Mogat1 and Cd36 expression was positively correlated with liver triglycerides in female mice. Our results indicate the value of CC mice in combination with HF/HS-diet-induced alterations as an approach to study the susceptibility and interindividual variabilities in the pathogenesis of nonalcoholic fatty liver and early nonalcoholic steatohepatitis at the population level, uncovering of susceptible and resistant cohorts, and identifying sex-specific molecular determinants of disease susceptibility.