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

Anna Katharina Spohner,Burkhard Kleuser,Josef Pfeilschifter,Khadija El-Hindi,Dieter Lütjohann,Julie D Saba,Fabian Schumacher,Dagmar Meyer Zu Heringdorf,Sabine Grösch,Dominique Thomas,Katja Jakobi,Sandra Trautmann

doi:10.3390/ijms221910617

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.

Highlights

Sphingolipids are in the focus of current research because they are part of fundamental cellular processes
We show here that in contrast to the global deletion of Sgpl1 in mice, specific deletion of Sgpl1 in mouse hepatocytes caused a mild phenotype with normal body weight, liver weight, liver histology and liver enzymes at least until the age of 8 months
Ceramides with C14, C16, C18 and C18:1 fatty acid chains were increased by ~10-fold, and sphingomyelins were elevated in the global knockouts [18]

Summary

Introduction

Sphingolipids are in the focus of current research because they are part of fundamental cellular processes (for a recent review, see [1]). S1P is an important bioactive lipid that acts both as agonist at five specific G-protein-coupled receptors (GPCR) and intracellularly (reviewed in [3]). The S1P-GPCR, S1P1-5, couple differentially to Gi, Gq, and G12/13 proteins and thereby regulate cell proliferation, survival, migration, adhesion, and other responses (reviewed in [4]). They are involved in vertebrate development, immune cell trafficking, regulation of vascular tone and permeability, and homoeostasis of many tissues (reviewed in [3]). S1P lyase and S1P transporters contribute to formation of S1P gradients between plasma and tissues and within tissues, which guide immune cell trafficking and cell positioning (reviewed in [10])

Methods

Results

Conclusion