Tetracyclines increase lipid phosphate phosphatase expression on plasma membranes and turnover of plasma lysophosphatidate

Tang, Xiaoyun; Zhao, Yuan; Dewald, Jay; Curtis, Jonathan M.; Brindley, David N.

doi:10.1194/jlr.m065086

Cited by 24 publications

(35 citation statements)

References 44 publications

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“…The same model can be applied to endothelial cells, but the effect of SphK2 deficiency is less pronounced in that tissue. Although our results are largely congruent with previous reports, the observation that ligation of the liver vasculature [18,41] did not raise endogenous circulating S1P is not the result that would be anticipated from our studies. We do not have an explanation for this apparent contradiction.…”

Section: Discussionsupporting

confidence: 92%

Mechanism of sphingosine 1-phosphate clearance from blood

Huang

Salamon

Harris

et al. 2020

Biochemical Journal

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The interplay of sphingosine 1-phosphate (S1P) synthetic and degradative enzymes as well as S1P exporters creates concentration gradients that are a fundamental to S1P biology. Extracellular S1P levels, such as in blood and lymph, are high relative to cellular S1P. The blood-tissue S1P gradient maintains endothelial integrity while local S1P gradients influence immune cell positioning. Indeed, the importance of S1P gradients was recognized initially when the mechanism of action of an S1P receptor agonist used as a medicine for multiple sclerosis was revealed to be inhibition of T-lymphocytes’ recognition of the high S1P in efferent lymph. Furthermore, the increase in erythrocyte S1P in response to hypoxia influences oxygen delivery during high altitude acclimatization. However, understanding of how S1P gradients are maintained is incomplete. For example, S1P is synthesized but is only slowly metabolized by blood yet circulating S1P turns over quickly by an unknown mechanism. Prompted by the counterintuitive observation that blood S1P increases markedly in response to inhibition S1P synthesis (by sphingosine kinase 2 (SphK2)), we studied mice wherein several tissues were made deficient in either SphK2 or S1P degrading enzymes. Our data reveal a mechanism whereby S1P is de-phosphorylated at the hepatocyte surface and the resulting sphingosine is sequestered by SphK phosphorylation and in turn degraded by intracellular S1P lyase. Thus, we identify the liver as the primary site of blood S1P clearance and provide an explanation for the role of SphK2 in this process. Our discovery suggests a general mechanism whereby S1P gradients are shaped.

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Section: Discussionsupporting

confidence: 92%

Mechanism of sphingosine 1-phosphate clearance from blood

Huang

Salamon

Harris

et al. 2020

Biochemical Journal

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“…Noteworthy, Ppap2b mRNA levels were found to be decreased also in HCC (http://onlinelibrary.wiley.com/doi/10.1002/hep.28973/suppinfo), as shown (http://onlinelibrary.wiley.com/doi/10.1002/hep.28973/suppinfo) for human HCC patients, possibly accounting for the sustainment of LPA levels. Although PPAP2s have been also incriminated for sphingosine‐1‐phosphate (S1P) degradation, no major differences in S1P levels were observed in HCC (http://onlinelibrary.wiley.com/doi/10.1002/hep.28973/suppinfo); however, large increases in expression of sphingosine‐1‐phosphate receptor 3 were observed upon HCC development, found to be diminished after ablation of ATX and LPA (http://onlinelibrary.wiley.com/doi/10.1002/hep.28973/suppinfo; http://onlinelibrary.wiley.com/doi/10.1002/hep.28973/suppinfo), in agreement with previous in vitro studies …”

Section: Resultsmentioning

confidence: 99%

“…S11G), as shown ( Supporting Table S1B) for human HCC patients, possibly accounting for the sustainment of LPA levels. Although PPAP2s have been also incriminated for sphingosine-1phosphate (S1P) degradation, (22) no major differences in S1P levels were observed in HCC (Supporting Fig. S11H); however, large increases in expression of sphingosine-1-phosphate receptor 3 were observed upon HCC development, found to be diminished after ablation of ATX and LPA (Supporting Fig.…”

Section: Atx Distorts Hcc-related Fatty Acid Metabolismmentioning

confidence: 99%

Hepatocyte autotaxin expression promotes liver fibrosis and cancer

et al. 2017

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“…13 ). In immune high tumors we found increased levels of SMPD1 encoding acidic sphingomyelinase that converts sphingomyelin to ceramide; NAAA encoding ceramidase that converts ceramide to sphingosine; SPHK1, a kinase that synthesizes S1P; ENPP2 that encodes autotaxin, which produces LPA in the extracellular space; and PPAP2A encoding the lipid phosphatase LPP1, which, upon translocation to the plasma membrane, preferentially dephosphorylates LPA [ 70 ]. When the described aberrations are superimposed on the interconnected lipid — enzyme network covering the sphingomyelin/salvage pathway, we see a clear shift towards S1P and S1P/S1PR as well as LPA and LPA/LPAR axes ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Interrelations of Sphingolipid and Lysophosphatidate Signaling with Immune System in Ovarian Cancer

Meshcheryakova

Svoboda

Jaritz

et al. 2019

Computational and Structural Biotechnology Journal

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The sphingolipid and lysophosphatidate regulatory networks impact diverse mechanisms attributed to cancer cells and the tumor immune microenvironment. Deciphering the complexity demands implementation of a holistic approach combined with higher-resolution techniques. We implemented a multi-modular integrative approach consolidating the latest accomplishments in gene expression profiling, prognostic/predictive modeling, next generation digital pathology, and systems biology for epithelial ovarian cancer. We assessed patient-specific transcriptional profiles using the sphingolipid/lysophosphatidate/immune-associated signature. This revealed novel sphingolipid/lysophosphatidate-immune gene-gene associations and distinguished tumor subtypes with immune high/low context. These were characterized by robust differences in sphingolipid‐/lysophosphatidate-related checkpoints and the drug response. The analysis also nominates novel survival models for stratification of patients with CD68 , LPAR3 , SMPD1 , PPAP2B , and SMPD2 emerging as the most prognostically important genes. Alignment of proprietary data with curated transcriptomic data from public databases across a variety of malignancies (over 600 categories; over 21,000 arrays) showed specificity for ovarian carcinoma. Our systems approach identified novel sphingolipid-lysophosphatidate-immune checkpoints and networks underlying tumor immune heterogeneity and disease outcomes. This holds great promise for delivering novel stratifying and targeting strategies.

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Tetracyclines increase lipid phosphate phosphatase expression on plasma membranes and turnover of plasma lysophosphatidate

Cited by 24 publications

References 44 publications

Mechanism of sphingosine 1-phosphate clearance from blood

Mechanism of sphingosine 1-phosphate clearance from blood

Hepatocyte autotaxin expression promotes liver fibrosis and cancer

Interrelations of Sphingolipid and Lysophosphatidate Signaling with Immune System in Ovarian Cancer

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