Mouse Liver Compensates Loss of Sgpl1 by Secretion of Sphingolipids into Blood and Bile

Abstract

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.

T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model

“…The quantification of sphingolipids in plasma and colon, small intestine, and liver tissue was performed by liquid chromatography tandem mass spectrometry (LC-MS/MS) as described previously [53]. In brief, the analytes were extracted by liquid-liquid extraction with methanol/chloroform/hydrochloric acid (15:83:2, v/v/v).…”

Loss of S1P Lyase Expression in Human Podocytes Causes a Reduction in Nephrin Expression That Involves PKCδ Activation

“…Another possible way in which SPL-kd mediates and triggers the downregulation of WT1 and nephrin is via another sphingolipid species, which, besides S1P, may also accumulate in SPL-kd [ 54 ]. For example, sphingosine is a well-known endogenous PKC inhibitor [ 55 , 56 ].…”

Pre-analytical sample handling standardization for reliable measurement of metabolites and lipids in LC-MS-based clinical research

“…Sphingolipids: Standard preparation and extraction for sphingoid bases and ceramides (described hereafter as sphingolipids) was performed as previously described with minor modifications [33] . Plasma samples were spiked with 20 µL IS working solution whereas STDs and QCs in Z-buffer (200 µL) as a surrogate matrix were spiked with 20 µL IS working solution and 20 µL of the respective standard working solution.…”