在成年小鼠体内诱导性全面敲除糜烂基因座蛋白 4 会导致低脂血症、肠道脂质积累、肝损伤和死亡率增加。

IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Wei Chen , Yuan Chen , Baoye Song , Lei Zhai , Geru Tao , Bingxiang Wang , Boyan Liu , Hao Wang , Cindy X. Zhang , Hong-mei Gu , Deling Yin , Shucun Qin , Da-wei Zhang
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引用次数: 0

摘要

超常位点蛋白 4(SURF4)是一种货物受体,可介导内质网输出各种货物。我们已经证明,SURF4 对肝脏极低密度脂蛋白和肠道乳糜微粒的分泌至关重要。敲除肝脏 Surf4 还能显著减少动脉粥样硬化和肝纤维化的发生,而不会造成明显的肝损伤。然而,全基因组Surf4敲除会导致胚胎死亡。为了进一步了解Surf4的生理作用,我们产生了他莫昔芬诱导的全基因Surf4敲除小鼠。我们发现,条件性敲除成年小鼠(Surf4ig-ko)的Surf4会显著降低小鼠体重。雄性和雌性Surf4ig-ko小鼠分别在服用他莫昔芬约30天和50天后死亡。与 Surf4flox 小鼠相比,Surf4ig-ko 小鼠的甘油三酯分泌和血清总胆固醇、甘油三酯、游离脂肪酸、载脂蛋白 B-100 和载脂蛋白-48 水平明显降低。小鼠血清样本的蛋白质组学分析表明,Surf4ig-ko 小鼠体内有 308 种蛋白质的表达发生了显著变化,这些蛋白质具有独特的功能,参与了各种生物过程。此外,Surf4ig-ko 小鼠的肠道有脂质积累,但肝脏没有。然而,Surf4ig-ko 小鼠的肝脏重量显著减少,血清转氨酶活性显著升高,表明肝脏受损。因此,SURF4 对成年小鼠的生存至关重要,这表明 SURF4 的治疗应用需要精确的组织/细胞类型特异性靶向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Inducible global knockout of surfeit locus protein 4 in adult mice results in hypolipidemia, intestinal lipid accumulation, liver injury, and increased mortality

Inducible global knockout of surfeit locus protein 4 in adult mice results in hypolipidemia, intestinal lipid accumulation, liver injury, and increased mortality
Surfeit locus protein 4 (SURF4) acts as a cargo receptor to mediate endoplasmic reticulum export of various cargos. We have shown that SURF4 is essential for secretion of hepatic very low-density lipoprotein and intestinal chylomicron. Knockdown of hepatic Surf4 also significantly reduces the development of atherosclerosis and liver fibrosis without causing overt liver damage. However, constitutive global Surf4 knockout results in embryonic lethality. To further understand the physiological role of SURF4, we generated tamoxifen-inducible global Surf4 knockout mice. We found that conditional knockout of Surf4 in adult mice (Surf4ig-ko) significantly reduced mouse body weight. Male and female Surf4ig-ko mice died approximately 30 and 50 days after tamoxifen administration, respectively. Triglyceride secretion and serum levels of total cholesterol, triglycerides, free fatty acids, apolipoprotein B-100, and apolipoprotein B-48 were significantly reduced in Surf4ig-ko mice compared with Surf4flox mice. Proteomics analysis of mouse serum samples revealed 308 proteins with significantly altered expression in Surf4ig-ko mice that have unique functions and are involved in various biological processes. In addition, Surf4ig-ko mice exhibited lipid accumulation in the intestine but not in the liver. However, in Surf4ig-ko mice, liver weight was significantly reduced, and serum transaminase activity was significantly increased, indicating liver damage. Therefore, SURF4 is essential for survival in adult mice, suggesting that the therapeutic use of SURF4 requires precise tissue/cell type-specific targeting.
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来源期刊
CiteScore
11.00
自引率
2.10%
发文量
109
审稿时长
53 days
期刊介绍: BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.
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