小鼠中与LIMP-2缺乏相关的糖脂异常。

IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Paulo Gaspar , André R.A. Marques , Maria J. Ferraz , Markus Damme , Gertjan Kramer , Mina Mirzaian , Marion Gijbels , Roelof Ottenhoff , Cindy van Roomen , Herman S. Overkleeft , Michael Schwake , Saskia Heybrock , Maria Carmo Macário , Paul Saftig , Johannes M. Aerts
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引用次数: 0

摘要

葡萄糖脑苷酶(GCase)催化溶酶体降解葡萄糖神经酰胺(glcer)。GCase缺乏导致戈谢病(GD),一种伴有特征性肝脾肿大的溶酶体积存疾病。GCase转运到溶酶体是由溶酶体整体膜蛋白2 (LIMP-2)介导的。LIMP-2缺乏导致细胞GCase水平降低,表现为行动性肌阵挛性肾衰竭综合征(AMRF)。我们探讨了GD和AMRF明显不同症状的原因。在Limp2 -/-小鼠的组织中,除了GCase的可变缺陷外,没有发现明显的溶酶体酶异常,这是通过酶活性测定和活性探针检测活性GCase分子来测量的。值得注意的是,在limp -2缺陷小鼠中,白细胞中残留的GCase非常高。组织中GCase的缺乏与glcer的增加无关,而是与葡萄糖基鞘氨酸(GlcSph)和葡萄糖基化胆固醇(GlcChol)的增加有关,这两种糖基化代谢产物均来源于glcer。从Limp2 -/-小鼠肝细胞分离的溶酶体显示除GCase外,溶酶体基质蛋白无明显异常。Limp2 -/-三体GlcSph和GlcChol明显升高,glcer无明显升高。总之,我们的数据表明,在鞘糖脂稳态中,LIMP-2起着至关重要的作用。尽管GCase水平较低,但在LIMP-2缺陷小鼠的组织中避免了显著的glcer积累。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
LIMP-2 deficiency-associated glycolipid abnormalities in mice
Glucocerebrosidase (GCase) catalyzes the lysosomal degradation of glucosylceramide (GlcCer). GCase deficiency results in Gaucher disease (GD), a lysosomal storage disorder with characteristic hepatosplenomegaly. Transport of GCase to lysosomes is mediated by the lysosomal integral membrane protein type 2 (LIMP-2). Deficiency of LIMP-2 leads to reduced cellular GCase levels and manifests as Action Myoclonic Renal Failure Syndrome (AMRF). We investigated the cause for the markedly different symptomatology of GD and AMRF. In tissues of Limp2 −/− mice no prominent abnormalities in lysosomal enzymes were noted except for variable deficiency of GCase, as measured with enzymatic activity assay and detection of active GCase molecules with an activity-based probe. Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes. GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer. Isolated lysosomes from hepatocytes of Limp2 −/− mice revealed no prominent abnormalities in lysosomal matrix proteins except GCase. The Limp2 −/− tritosomes showed clear increases in GlcSph and GlcChol but not in GlcCer. In conclusion, our data imply a critical role of LIMP-2 in glycosphingolipid homeostasis. Despite low GCase levels striking GlcCer accumulation is avoided in tissues of LIMP-2 deficient mice.
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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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