Characterization of secretory sphingomyelinase activity, lipoprotein sphingolipid content and LDL aggregation in ldlr-/- mice fed on a high-fat diet.
Characterization of secretory sphingomyelinase activity, lipoprotein sphingolipid content and LDL aggregation in ldlr-/- mice fed on a high-fat diet.
复制标题
在LDLR - / - 小鼠中，分泌性鞘磷脂酶活性，脂蛋白鞘脂含量和LDL聚集的表征。
DOI：
10.1042/bsr20120036
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发表时间：
2012-10
影响因子：
4
通讯作者：
Nikolova-Karakashian MN
中科院分区：
文献类型：
--
作者：
Deevska GM;Sunkara M;Morris AJ;Nikolova-Karakashian MN
LDL（低密度脂蛋白）的聚集和/或氧化倾向与其鞘脂含量有关，特别是SM（鞘磷脂）和神经酰胺的水平。为了在体内研究这种关联，ldlr（LDL受体）-null小鼠（ldlr−/−）被喂食含有饱和脂肪和胆固醇的改良（致动脉粥样硬化）饮食。饮食导致所有血清脂蛋白中SM含量显著升高。相反，神经酰胺仅在LDL颗粒中增加。脂质酰基链组成的基于MS的分析显示SM和神经酰胺中C16：0脂肪酸显著升高，与改良饮食中棕榈酸的患病率一致。饮食还导致S-SMase [分泌型SMase（鞘磷脂酶）]的活性增加，这是一种由ASMase（酸性SMase）产生并作用于血清LDL的蛋白质。增加的巨噬细胞分泌似乎是负责升高的S-SMase活性。ASMase缺陷小鼠（asm−/−/ldlr−/−）缺乏S-SMase活性，并可防止饮食诱导的LDL神经酰胺升高。与asm+/+/ldlr −/−小鼠的LDL相比，喂食改良饮食的asm−/−/ldlr −/−小鼠的LDL聚集和氧化程度更低。在体外试验时，聚集倾向取决于SM水平：只有来自改良饲料动物的LDL在用重组S-SMase处理时聚集，这些动物具有高SM含量。总之，在喂食致动脉粥样硬化饮食的小鼠中，LDL-SM含量和S-SMase活性上调。S-SMase介导饮食诱导的LDL神经酰胺含量和聚集的变化。S-SMase诱导聚集的有效性依赖于饮食诱导的SM对LDL的富集，可能是通过增加肝脏合成。
The propensity of LDLs (low-density lipoproteins) for aggregation and/or oxidation has been linked to their sphingolipid content, specifically the levels of SM (sphingomyelin) and ceramide. To investigate this association in vivo, ldlr (LDL receptor)-null mice (ldlr−/−) were fed on a modified (atherogenic) diet containing saturated fats and cholesterol. The diet led to significantly elevated SM content in all serum lipoproteins. In contrast, ceramide increased only in the LDL particles. MS-based analyses of the lipid acyl chain composition revealed a marked elevation in C16:0 fatty acid in SM and ceramide, consistent with the prevalence of palmitic acid in the modified diet. The diet also led to increased activity of the S-SMase [secretory SMase (sphingomyelinase)], a protein that is generated by ASMase (acid SMase) and acts on serum LDL. An increased macrophage secretion seemed to be responsible for the elevated S-SMase activity. ASMase-deficient mice (asm−/−/ldlr−/−) lacked S-SMase activity and were protected from diet-induced elevation in LDL ceramide. LDL from asm−/−/ldlr−/− mice fed on the modified diet were less aggregated and oxidized than LDL from asm+/+/ldlr−/− mice. When tested in vitro, the propensity for aggregation was dependent on the SM level: only LDL from animals on modified diet that have high SM content aggregated when treated with recombinant S-SMase. In conclusion, LDL-SM content and S-SMase activity are up-regulated in mice fed on an atherogenic diet. S-SMase mediates diet-induced changes in LDL ceramide content and aggregation. S-SMase effectiveness in inducing aggregation is dependent on diet-induced enrichment of LDL with SM, possibly through increased hepatic synthesis.