Mouse Liver Compensates Loss of Sgpl1 by Secretion of Sphingolipids into Blood and Bile.
Mouse Liver Compensates Loss of Sgpl1 by Secretion of Sphingolipids into Blood and Bile.
复制标题
DOI：
10.3390/ijms221910617
复制
发表时间：
2021-09-30
影响因子：
5.6
通讯作者：
Meyer Zu Heringdorf D
中科院分区：
文献类型：
--
作者：
Spohner AK;Jakobi K;Trautmann S;Thomas D;Schumacher F;Kleuser B;Lütjohann D;El-Hindi K;Grösch S;Pfeilschifter J;Saba JD;Meyer Zu Heringdorf D
鞘氨醇1磷酸（S1P）裂解酶（Sgpl1）催化S1P的不可逆裂解，从而催化鞘脂降解的最后一步。人和小鼠中Sgpl1的缺失导致鞘脂的积累和多器官损伤。在这里，我们解决了肝细胞Sgpl1的调节鞘脂稳态的作用，通过产生小鼠与肝细胞特异性缺失的Sgpl1（Sgpl1HepKO小鼠）。Sgpl1HepKO小鼠在8周龄和8月龄时体重、肝脏重量、肝脏结构和肝酶均正常。S1P、鞘氨醇和神经酰胺（而非葡萄糖神经酰胺或鞘磷脂）在肝脏中升高约1.5 - 2倍，且该表型不随年龄增长而进展。血浆中几种神经酰胺升高，而血浆S1P正常。有趣的是，S1P和葡糖神经酰胺，但不是神经酰胺，在SgpllHepKO小鼠的胆汁中升高。此外，在8个月大的小鼠中，肝脏胆固醇升高，而LDL胆固醇降低。与此一致，LDL受体上调，表明LDL胆固醇的摄取增强。过氧化物酶体增殖物激活受体-γ、肝脏X受体和脂肪酸合成酶的表达没有改变。这些数据表明，小鼠肝细胞通过以特定方式将积累的鞘脂分泌到血液和胆汁中，在很大程度上补偿了Sgpl 1的损失，使得它们可以在其他地方排泄或降解。
Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte Sgpl1 for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of Sgpl1 (Sgpl1HepKO mice). Sgpl1HepKO mice had normal body weight, liver weight, liver structure and liver enzymes both at the age of 8 weeks and 8 months. S1P, sphingosine and ceramides, but not glucosylceramides or sphingomyelin, were elevated by ~1.5–2-fold in liver, and this phenotype did not progress with age. Several ceramides were elevated in plasma, while plasma S1P was normal. Interestingly, S1P and glucosylceramides, but not ceramides, were elevated in bile of Sgpl1HepKO mice. Furthermore, liver cholesterol was elevated, while LDL cholesterol decreased in 8-month-old mice. In agreement, the LDL receptor was upregulated, suggesting enhanced uptake of LDL cholesterol. Expression of peroxisome proliferator-activated receptor-γ, liver X receptor and fatty acid synthase was unaltered. These data show that mouse hepatocytes largely compensate the loss of Sgpl1 by secretion of accumulating sphingolipids in a specific manner into blood and bile, so that they can be excreted or degraded elsewhere.
登录
查看更多内容
影响因子：
5.6
作者：
Ben Saad A;Bruneau A;Mareux E;Lapalus M;Delaunay JL;Gonzales E;Jacquemin E;Aït-Slimane T;Falguières T
通讯作者：
Falguières T
DOI：
10.1038/nrm.2017.107
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Hannun YA;Obeid LM
通讯作者：
Obeid LM
影响因子：
4.8
作者：
Hagen-Euteneuer, Nadine;Luetjohann, Dieter;van Echten-Deckert, Gerhild
通讯作者：
van Echten-Deckert, Gerhild
影响因子：
4.1
作者：
Kharel, Yugesh;Huang, Tao;Lynch, Kevin R.
通讯作者：
Lynch, Kevin R.
影响因子：
9.9
作者：
Atkinson, Derek;Glumac, Jelena Nikodinovic;Jordanova, Albena
通讯作者：
Jordanova, Albena