HEPATIC SECRETION OF SMALL LIPOPROTEIN IN APOBEC-1?/? MICE - LDL RECEPTOR

APOBEC-1 中小脂蛋白的肝脏分泌？/？

• 批准号: 7355240
• 负责人: Fatiha Nassir
• 金额: $ 0.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355240
• 关键词: HEPATIC; SECRETION; SMALL; LIPOPROTEIN; APOBEC

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent studies have examined the role of the LDL receptor (LDLR) in regulating murine hepatic lipoprotein production and apolipoprotein B (apoB) secretion, with divergent conclusions from in vivo versus in vitro approaches. We have re-examined this question, both in vivo and in vitro, using apobec-1-/- mice to model the pattern of human hepatic apoB-100 secretion. Hepatic triglyceride production in vivo (using Triton WR-1339) was unchanged in wild-type (WT) C57BL/6, apobec-1-/-, ldlr-/-, and [apobec-1-/-, ldlr-/-] mice, while apoB-100 production (using [35S]methionine incorporation) was increased >2-fold in [apobec-1-/-, ldlr-/-] mice. Although >90% of newly synthesized apoB floated within the d < 1.006 fraction of serum from all genotypes, fast-performance liquid chromatography separation revealed that nascent triglyceride-rich particles from [apobec-1-/-, ldlr-/-] mice, but not WT, apobec-1-/-, or ldlr-/- mice, distributed into smaller (intermediate and LDL-sized) particles. Studies in isolated hepatocytes from these different genotypes confirmed secretion of smaller particles exclusively from [apobec-1-/-, ldlr-/-] mice, and pulse-chase analysis demonstrated increased secretion of apoB-100 with virtual elimination of posttranslational degradation. These results directly support the suggestion that the LDLR regulates hepatic apoB-100 production and modulates secretion of small, triglyceride-rich particles, both in vivo and in vitro.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。最近的研究已经检查了LDL受体（LDLR）在调节小鼠肝脂蛋白产生和载脂蛋白B（apoB）分泌中的作用，从体内与体外方法得出不同的结论。我们已经重新研究了这个问题，在体内和体外，使用apobec-1-/-小鼠模型的人肝apoB-100分泌的模式。在野生型（WT）C57 BL/6、apobec-1-/-、ldlr-/-和[apobec-1-/-、ldlr-/-]小鼠中，体内肝脏甘油三酯产生（使用Triton WR-1339）未发生变化，而在[apobec-1-/-、ldlr-/-]小鼠中，apoB-100产生（使用[35 S]甲硫氨酸掺入）增加>2倍。尽管>90%的新合成的apoB漂浮在所有基因型血清中d < 1.006的部分中，但快速高效液相色谱分离显示，来自[apobec-1-/-，ldlr-/-]小鼠而不是WT，apobec-1-/-或ldlr-/-小鼠的新生富谷胱甘肽颗粒分布成较小的（中等和LDL大小）颗粒。对来自这些不同基因型的分离肝细胞的研究证实了仅来自[apobec-1-/-，ldlr-/-]小鼠的较小颗粒的分泌，脉冲追踪分析表明apoB-100的分泌增加，翻译后降解几乎消除。这些结果直接支持了LDLR调节肝脏apoB-100产生并调节体内和体外富含磷脂酰胆碱的小颗粒分泌的建议。