TY  - JOUR
A1  - Spohner, Anna Katharina
A1  - Jakobi, Katja
A1  - Trautmann, Sandra
A1  - Thomas, Dominique Jeanette
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Lütjohann, Dieter
A1  - El-Hindi, Khadija
A1  - Grösch, Sabine
A1  - Pfeilschifter, Josef
A1  - Saba, Julie D.
A1  - Meyer zu Heringdorf, Dagmar
T1  - Mouse liver compensates loss of Sgpl1 by secretion of sphingolipids into blood and bile
T2  - International journal of molecular sciences
N2  - 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.
KW  - sphingosine-1-phosphate
KW  - SGPL1
KW  - ceramides
KW  - liver
KW  - bile
KW  - cholesterol
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63453
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-634537
SN  - 1422-0067
N1  - This work was supported by the Deutsche Forschungsgemeinschaft SFB 1039 to A.K.S., K.J., S.T., D.T., K.E.-H., S.G., J.P., D.M.z.H. and Public Health Service grant NIH R01 DK115669 to J.D.S. The article processing charges were provided by the Open Access Publication Fund of the Goethe University Frankfurt.
VL  - 22
IS  - 10617
SP  - 1
EP  - 22
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -