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Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P₂ receptor subtype

Title data

Fayyaz, Susann ; Henkel, Janin ; Japtok, Lukasz ; Krämer, Stephanie ; Damm, Georg ; Seehofer, Daniel ; Püschel, Gerhard P. ; Kleuser, Burkhard:
Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P₂ receptor subtype.
In: Diabetologia. Vol. 57 (February 2014) Issue 2 . - pp. 373-82.
ISSN 0012-186X
DOI: https://doi.org/10.1007/s00125-013-3123-6

Abstract in another language

AIMS/HYPOTHESIS

Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance.

METHODS

The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice.

RESULTS

Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P2 receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P2, was not able to inhibit insulin signalling.

CONCLUSIONS/INTERPRETATION

These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P2 receptor to impair insulin signalling. In particular, S1P2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Life Sciences: Food, Nutrition and Health
Faculties
Result of work at the UBT: No
DDC Subjects: 500 Science > 500 Natural sciences
500 Science > 570 Life sciences, biology
Date Deposited: 26 Apr 2021 11:45
Last Modified: 26 Apr 2021 13:06
URI: https://eref.uni-bayreuth.de/id/eprint/64433