Chylomicron retention disease (CRD) is an autosomal recessive disorder associated with biallelic Sar1b mutations leading to defects in intracellular chylomicron (CM) trafficking and secretion. To date, a direct cause-effect relationship between CRD and Sar1b mutation has not been established, but genetically modified animal models provide an opportunity to elucidate unrecognized aspects of these mutations. To examine the physiological role and molecular mechanisms of Sar1b function, we generated mice expressing either a targeted deletion or mutation of human Sar1b using the CRISPR/Cas9 system. We found that deletion or mutation of Sar1b in mice resulted in late-gestation lethality of homozygous embryos. Moreover, compared to WT mice, heterozygotes carrying a single disrupted Sar1b allele displayed lower plasma levels of triglycerides, total cholesterol, and HDL-cholesterol, along with reduced CM secretion following gastric lipid gavage. Similarly, decreased expression of apolipoprotein B and microsomal triglyceride transfer protein was observed in correlation with the accumulation of mucosal lipids. Inefficient fat absorption in heterozygotes was confirmed via an increase in fecal lipid excretion. Furthermore, genetically modified Sar1b affected intestinal lipid homeostasis as demonstrated by enhanced fatty acid β-oxidation and diminished lipogenesis through the modulation of transcription factors. This is the first reported mammalian animal model with human Sar1b genetic defects, which reproduces some of the characteristic CRD features and provides a direct cause-effect demonstration.

中文翻译：

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Sar1b 突变小鼠重现了与乳糜微粒滞留病相关的胃肠道异常。


乳糜微粒滞留病 (CRD) 是一种常染色体隐性遗传病，与双等位基因 Sar1b 突变相关，导致细胞内乳糜微粒 (CM) 运输和分泌缺陷。迄今为止，CRD 和 Sar1b 突变之间的直接因果关系尚未确定，但转基因动物模型提供了阐明这些突变的未识别方面的机会。为了研究 Sar1b 功能的生理作用和分子机制，我们使用 CRISPR/Cas9 系统培育了表达人类 Sar1b 靶向缺失或突变的小鼠。我们发现小鼠中 Sar1b 的缺失或突变会导致纯合胚胎妊娠晚期致死。此外，与野生型小鼠相比，携带单一破坏的 Sar1b 等位基因的杂合子显示出较低的血浆甘油三酯、总胆固醇和高密度脂蛋白胆固醇水平，并且在胃脂质灌胃后，CM 分泌减少。类似地，载脂蛋白 B 和微粒体甘油三酯转移蛋白的表达降低与粘膜脂质的积累相关。通过粪便脂质排泄的增加证实杂合子中脂肪吸收效率低下。此外，转基因 Sar1b 影响肠道脂质稳态，通过转录因子的调节增强脂肪酸 β-氧化并减少脂肪生成。这是第一个报道的具有人类 Sar1b 遗传缺陷的哺乳动物模型，它再现了 CRD 的一些特征，并提供了直接的因果关系证明。