SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes

Geng, Tuoyu; Sutter, Alton G.; Harland, Michael D.; Law, Brittany A.; Ross, Jessica S.; Lewin, David; Palanisamy, Arun P.; Russo, Sarah; Chavin, Kenneth D.; Cowart, L. Ashley

doi:10.1194/jlr.m063511

Cited by 79 publications

(92 citation statements)

References 41 publications

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“…Moreover, lipopolysaccharides (LPS) induce SphK1 activation via TLR4 in macrophages, thereby promoting IL-6 generation [23]. Targeting SphK1 in mice by genetic ablation or pharmacological inhibition ameliorates the inflammatory cytokine production as well as the pathogenesis of experimental models of arthritis [24,25], hepatitis [26], and pulmonary fibrosis [27]. Based on these reports, it is tempting to speculate that there is a reciprocal interference between biglycan and sphingolipid signaling in the regulation of inflammation.…”

Section: Introductionmentioning

confidence: 99%

Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants

Hsieh

Nastase

Roedig

et al. 2017

IJMS

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Abstract:In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5 through selective utilization of Toll-like receptors (TLRs) and their adaptor molecules. However, the respective downstream signaling events resulting in biglycan-induced CCL2 and CCL5 production have not yet been defined. Here, we show that biglycan stimulates the production and activation of sphingosine kinase 1 (SphK1) in a TLR4-and Toll/interleukin (IL)-1R domain-containing adaptor inducing interferon (IFN)-β (TRIF)-dependent manner in murine primary macrophages. We provide genetic and pharmacological proof that SphK1 is a crucial downstream mediator of biglycan-triggered CCL2 and CCL5 mRNA and protein expression. This is selectively driven by biglycan/SphK1-dependent phosphorylation of the nuclear factor NF-κB p65 subunit, extracellular signal-regulated kinase (Erk)1/2 and p38 mitogen-activated protein kinases. Importantly, in vivo overexpression of soluble biglycan causes Sphk1-dependent enhancement of renal CCL2 and CCL5 and macrophage recruitment into the kidney. Our findings describe the crosstalk between biglycanand SphK1-driven extracellular matrix-and lipid-signaling. Thus, SphK1 may represent a new target for therapeutic intervention in biglycan-evoked inflammatory conditions.

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Section: Introductionmentioning

confidence: 99%

Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants

Hsieh

Nastase

Roedig

et al. 2017

IJMS

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“…SphK1/S1P-mediated signaling has been suggested to promote hepatic steatosis and inflammation. Expression of hepatic SphK1 is elevated in both high-fat-high-glucose-fed mice and human NASH patients (71). SphK1 −/− mice were protected from high-fat-high-glucose diet-induced hepatic inflammation and lipid accumulation (71).…”

Section: Sphks and S1p In Lipid Metabolismmentioning

confidence: 99%

“…Expression of hepatic SphK1 is elevated in both high-fat-high-glucose-fed mice and human NASH patients (71). SphK1 −/− mice were protected from high-fat-high-glucose diet-induced hepatic inflammation and lipid accumulation (71). Interestingly, another recent study done by Chen, et al reported that deletion of SphK1 ameliorated hepatic steatosis in high-fat-diet fed mice by the down-regulation of peroxisome proliferator-activated receptor gamma (PPARγ) expression in the liver (50).…”

Section: Sphks and S1p In Lipid Metabolismmentioning

confidence: 99%

Sphingosine Kinases/Sphingosine 1-Phosphate Signaling in Hepatic Lipid Metabolism

Kwong

Hylemon

et al. 2017

Curr Pharmacol Rep

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The ever-increasing prevalence of metabolic diseases such as dyslipidemia and diabetes in the western world continues to be of great public health concern. Biologically active sphingolipids, such as sphingosine 1-phosphate (S1P) and ceramide, are important regulators of lipid metabolism. S1P not only directly functions as an active intracellular mediator, but also activates multiple signaling pathways via five transmembrane G-protein coupled receptors (GPCRs), S1PR1-5. S1P is exclusively formed by sphingosine kinases (SphKs). Two isoforms of SphKs, SphK1 and SphK2, have been identified. Recent identification of the conjugated bile acid-induced activation of S1PR2 as a key regulator of SphK2 opened new directions for both the sphingolipid and bile acid research fields. The role of SphKs/S1P-mediated signaling pathways in health and various human diseases has been extensively reviewed elsewhere. This review focuses on recent findings related to SphKs/S1P-medaited signaling pathways in regulating hepatic lipid metabolism.

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“…Il faudra également déterminer la pertinence du rôle de la SphK1 chez l'homme. Récemment, il a été montré que l'expression de la SphK1 hépatique était augmentée chez des patients souffrant de stéatose hépatique [13]. À terme, ces avancées pourraient permettre d'envisager la SphK1 comme une cible thérapeutique potentielle dans le traitement de la stéatose hépatique.…”

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“…Dans le foie, PPAR est exprimé dans les cellules de Kupffer (macrophages spécialisés) et les hépatocytes, mais l'activation de PPAR dans les cellules de Kupffer n'est pas essentielle au développement initial de la stéatose hépatique [12], suggérant que la régu-lation de PPAR par la SphK1 se fait au niveau des hépatocytes. Néanmoins, le rôle de la SphK1 dans les cellules de Kupffer, elles-mêmes impliquées dans la stéatose hépatique, reste encore à déterminer, et en particulier son rôle pro-inflammatoire [13]. ment accrue par l'acide palmitique et la S1P.…”

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La sphingosine kinase 1 : rôle dans la stéatose hépatique

Pruvost

Stunff

2016

Med Sci (Paris)

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SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes

Cited by 79 publications

References 41 publications

Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants

Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants

Sphingosine Kinases/Sphingosine 1-Phosphate Signaling in Hepatic Lipid Metabolism

La sphingosine kinase 1 : rôle dans la stéatose hépatique

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