The cytoplasmic peptide:N-glycanase (Ngly1) is a de-N-glycosylating enzyme that cleaves N-glycans from misfolded glycoproteins and is involved in endoplasmic reticulum-associated degradation. The recent discovery of NGLY1-deficiency, which causes severe systemic symptoms, drew attention to the physiological function of Ngly1 in mammals. While several studies have been carried out to reveal the physiological necessity of Ngly1, the semi-lethal nature of Ngly1-deficient animals made it difficult to analyze its function in adults. In this study, we focus on the physiological function of Ngly1 in liver (hepatocyte)-specific Ngly1-deficient mice generated using the cre-loxP system. We found that hepatocyte-specific Ngly1-deficient mice showed abnormal hepatocyte nuclear size/morphology with aging but did not show other notable defects in unstressed conditions. This nuclear phenotype did not appear to be related to the function of the only gene currently reported to rescue Ngly1-deficient murine lethality so far, endo-β-N-acetylglucosaminidase. We also found that under a high fructose diet induced stress, the hepatocyte-specific Ngly1-deletion resulted in liver transaminases elevation and increased lipid droplet accumulation. We showed that the processing and localization of the transcription factor, nuclear factor erythroid 2-like 1 (Nfe2l1), was impaired in the Ngly1-deficient hepatocytes. Therefore, Nfe2l1, at least partially, contributes to the phenotypes observed in hepatocyte-specific Ngly1-deficient mice. Our results indicate that Ngly1 plays important roles in the adult liver impacting nuclear morphology and lipid metabolism. Hepatocyte-specific Ngly1-deficient mice could thus serve as a valuable animal model for assessing in vivo efficacy of drugs and/or treatment for NGLY1-deficiency.

中文翻译：

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在食物压力下，肝脏特异性Ngly1缺失会导致异常的核形态和脂质代谢。

细胞质肽：N-聚糖酶（Ngly1）是一种脱N-糖基化酶，可从错误折叠的糖蛋白上裂解N-聚糖，并参与与内质网相关的降解。NGLY1缺乏症的最新发现引起严重的全身症状，引起人们对Ngly1在哺乳动物中的生理功能的关注。尽管已经进行了几项研究来揭示Ngly1的生理必要性，但Ngly1缺陷动物的半致死性质使其难以分析其在成年动物中的功能。在这项研究中，我们专注于使用cre-loxP系统生成的肝脏（肝细胞）特异性Ngly1缺陷型小鼠中Ngly1的生理功能。我们发现，肝细胞特异性Ngly1缺陷型小鼠随着年龄的增长显示出异常的肝细胞核大小/形态，但在无压力条件下未显示出其他明显的缺陷。这种核表型似乎与迄今为止报道的挽救Ngly1缺陷型鼠致死力的唯一基因的功能无关，即内源性β-N-乙酰氨基葡糖苷酶。我们还发现，在高果糖饮食诱导的压力下，肝细胞特异性Ngly1缺失导致肝脏转氨酶升高和脂质滴积累增加。我们显示，在缺乏Ngly1的肝细胞中，转录因子核因子类红细胞2样1（Nfe2l1）的加工和定位受到损害。因此，Nfe2l1至少部分地有助于在肝细胞特异性Ngly1缺陷型小鼠中观察到的表型。我们的结果表明，Ngly1在影响肝脏形态和脂质代谢的成年肝脏中起重要作用。因此，肝细胞特异性Ngly1缺陷小鼠可以作为有价值的动物模型，用于评估药物的体内功效和/或NGLY1缺乏症的治疗。