Sphingosine kinase 2 (SphK2) knockout alters metabolic gene expression in an early MASH mouse model
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ABSTRACT:
PROVIDER: PRJNA1176455 | ENA |
REPOSITORIES: ENA
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Project description:To determine the effect of SphK2 KO on liver metabolic-associated gene expression in an early MASH mouse model To determine the effect of WDSW on liver metabolic-associated gene expression in an early MASH mouse model
2024-11-20 | GSE280101 | GEO
Project description:Sphingosine kinase 2 (SphK2) knockout increases liver inflammation in an early MASH mouse model
| PRJNA1176171 | ENA
Project description:To determine the effect of SphK2 KO on liver inflammation in an early MASH mouse model To determine the effect of WDSW on liver inflammation in an early MASH mouse model
2024-11-20 | GSE280083 | GEO
Project description:Obesity increases circulating levels of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). Here, we identify adipocyte-expressed sphingosine kinase 2 (SPHK2), an enzyme that produces S1P, as a regulator of adipose tissue browning. Mice with adipocyte-specific deletion of Sphk2 were protected from Western diet-induced obesity concomitantly with elevated energy expenditure and browning of subcutaneous fat and enhanced expression of Ucp1 and key thermogenic genes, resulting in reduced adiposity and hepatic steatosis, improved glucose tolerance and insulin sensitivity. Mechanistically, obesogenic diet promoted nuclear localization of SPHK2 in adipocytes, where it cooperated with transcription factors to suppress the thermogenic transcriptome. Adipocyte SPHK2 was responsible for maintaining homeostatic circulating S1P levels and driving the pathogenic rise of S1P in response to obesogenic diet. Our findings reveal a distinct role of adipocyte SPHK2 in regulation of the thermogenic program important for whole-body metabolic homeostasis and energy expenditure and highlights SPHK2 as a potential therapeutic target for treatment of metabolic disorders.
2026-06-30 | GSE328946 | GEO
Project description:Obesity increases circulating levels of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). Here, we identify adipocyte-expressed sphingosine kinase 2 (SPHK2), an enzyme that produces S1P, as a regulator of adipose tissue browning. Mice with adipocyte-specific deletion of Sphk2 were protected from Western diet-induced obesity concomitantly with elevated energy expenditure and browning of subcutaneous fat and enhanced expression of Ucp1 and key thermogenic genes, resulting in reduced adiposity and hepatic steatosis, improved glucose tolerance and insulin sensitivity. Mechanistically, obesogenic diet promoted nuclear localization of SPHK2 in adipocytes, where it cooperated with transcription factors to suppress the thermogenic transcriptome. Adipocyte SPHK2 was responsible for maintaining homeostatic circulating S1P levels and driving the pathogenic rise of S1P in response to obesogenic diet. Our findings reveal a distinct role of adipocyte SPHK2 in regulation of the thermogenic program important for whole-body metabolic homeostasis and energy expenditure and highlights SPHK2 as a potential therapeutic target for treatment of metabolic disorders.
2026-06-30 | GSE329000 | GEO
Project description:Reciprocal interactions between breast cancer cells and the tumor microenvironment are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAFs) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the tumor microenvironment and restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non-cell autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the tumor microenvironment and enhance therapeutic efficacy.
2020-01-01 | GSE136655 | GEO
Project description:Viruses often establish persistent infections by interrupting immune cell responses. Sphingosine kinase 2 (SphK2) generates sphingosine 1-phsophate, which is known to regulate versatile cellular processes, including immune responses. However, little is known about the role of SphK2 in the immune response to viral infections. Here, we demonstrate that during lymphocytic choriomeningitis virus (LCMV) clone 13 infection, a virus known to establish a persistent infection in mice, SphK2 functions to limit CD4+ T cell responses, which aids in the establishment of virus-induced immunosuppression and viral persistence. The infection of SphK2-deficient (Sphk2-/-) mice with LCMV resulted in kidney disease and ultimately mortality. Following infection, Sphk2-/- mice were shown to have increased LCMV-specific CD4+ and CD8+ T cell responses. With the use of LCMV epitope-specific TCR transgenic mouse lines in adoptive transfer studies, SphK2 was shown to have intrinsic negative function in CD4+ T cells, but not CD8+ T cells. Furthermore, Sphk2-/- CD4+ T cells were able to promote endogenous, virus-specific CD8+ T cell responses more efficiently than Sphk2+/+ CD4+ T cells. Our results suggest that SphK2 is a novel regulator of the immune response during LCMV clone 13 infection and targeting SphK2 may provide a promising immunotherapeutic strategy for the control of persistent viral infections. This study incorporated the use of RNA sequencing to determine what pathways SphK2 was involved in to affect CD4+ T cell activity and proliferation. Sphk2+/+ or Sphk2-/- LCMV epitope-recognizing tg CD4+ T cells were transferred into C57BL/6 mice and recovered 7 days following LCMV Cl 13 infection. RNA sequencing revealed several pathways upregulated in Sphk2-/- CD4+ T cells relating to cell cycle progression, regulation of transcription, and regulation of nucleic acid binding.
2020-10-29 | GSE155030 | GEO
Project description:Hepatic very low-density lipoprotein (VLDL) is essential for maintaining lipid metabolism in the liver. Sphingosine kinases (SphKs) are essential rate-limiting enzymes that catalyze sphingosine phosphorylation to Sphingosine-1-phosphate (S1P). SphKs exist as two isoforms, SphK1 and SphK2, both highly expressed in the liver. SphK1 plays a critical role in regulating hepatic inflammation and drug metabolism. This study aimed to determine whether SphK2 regulates hepatic lipid metabolism, particularly VLDL secretion. Immunohistochemical staining revealed decreased SphK2 protein levels within regions proximal to hepatic lipid accumulation in individuals diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD). Sphk2−/− mice exhibited spontaneous hepatocyte lipid accumulation and reduced VLDL secretion. Proteomic analysis revealed that SphK2 deficiency impaired soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complex interactions involved in vesicular transport and organelle membrane fusion. Furthermore, SphK2 deficiency results in accelerated degradation of the SEC22B, STX5A, and GS28 proteins via chaperone-mediated autophagy (CMA), impeding VLDL transport to the Golgi apparatus. MYH1485, a specific activator of mTOR, induces mTORC2 phosphorylation, thereby inhibiting the degradation of SNARE complexes by CMA and counteracting the lipid accumulation induced by SphK2 deficiency. Exogenous S1P supplementation markedly reversed the reduction in mTORC2 phosphorylation and suppressed CMA, thereby improving VLDL secretion. Our study elucidates an inventive regulatory mechanism by which SphK2 modulates CMA by activating mTORC2 phosphorylation, promoting VLDL secretion, and balancing lipid metabolism in the liver. These findings provide insights into SphK2 function and the underlying mechanisms involved in the regulation of VLDL secretion, which may facilitate MASLD treatment.
2025-10-13 | PXD059594 | Pride
Project description:Deletion of sphingosine kinase 2 (Sphk2) suppresses ferroptosis and restores functional capacities in old HSCs
2026-01-15 | GSE287241 | GEO
Project description:Deletion of sphingosine kinase 2 (Sphk2) suppresses ferroptosis and restores functional capacities in old HSCs
2026-01-15 | GSE287104 | GEO