Mice have provided critical mechanistic understandings of clinical traits underlying Metabolic Syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-Oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.

中文翻译：

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肝脏转录谱揭示了饮食和遗传背景对协同杂交雌性祖株代谢特征的作用

小鼠对代谢综合征 (MetSyn) 的临床特征提供了重要的机制理解，并且已知小鼠对 MetSyn 的易感性因近交系而异。我们调查了八种协作交叉 (CC) 创始人菌株（A/J、C57BL/6J、129S1/SvImJ、NOD/ShiLtJ、NZO/HILtJ、CAST/EiJ、PWK/ PhJ 和 WSB/EiJ)。肝脏转录组学分析表明，致动脉粥样硬化饮食和宿主遗传学对肝脏转录组有深远的影响，这可能与菌株之间观察到的代谢性状差异有关。我们发现循环三甲胺 N-氧化物 (TMAO) 浓度和肝脏甘油三酯含量的菌株差异，这两者都是与代谢疾病相关的特征。使用网络方法，我们确定了一个与 TMAO 和肝脏甘油三酯含量相关的转录本模块，该模块富含功能通路。对与代谢性状相关的模块的询问确定了 NADPH 氧化酶 4 (Nox4)，它是产生活性氧物质的关键酶的基因，它与血浆 TMAO 和肝脏甘油三酯密切相关。有趣的是，Nox4 被确定为在 C57BL/6J 和 NZO/HILtJ 菌株中表达最高，在 CAST/EiJ 菌株中表达最低。基于这些结果，我们认为 Nox4 对调节血浆 TMAO 和肝脏甘油三酯含量的贡献可能存在遗传变异。总之，我们表明肝脏转录组分析确定了协作交叉 (CC) 创始人菌株中代谢特征的饮食或菌株特异性途径。