Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages

Jin, Junfei; Zhang, Xiaoming; Lu, Zhongyang; Perry, David; Li, Yanchun; Russo, Sarah; Cowart, L. Ashley; Hannun, Yusuf A.; Huang, Yan

doi:10.1152/ajpendo.00251.2013

Cited by 79 publications

(134 citation statements)

References 52 publications

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“…This hypothesis has been supported by the fact that there was a concomitant attenuation in the lysosomal sphingomyelinase activity in endothelial cells after cytokine stimulation (Marathe et al, 1998). In addition, inhibition of aSMase prevented the activation of Toll-like receptor 4 (TLR4) downstream of LPS stimulation (Jin et al, 2013). These results highlights the role of aSMase in inflammation and the possible beneficial use of its inhibitors in treating septic patients.…”

Section: Asmase In Pathophysiologymentioning

confidence: 82%

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

Adada

Luberto

Canals

2016

Chemistry and Physics of Lipids

102

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Section: Asmase In Pathophysiologymentioning

confidence: 82%

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

Adada

Luberto

Canals

2016

Chemistry and Physics of Lipids

102

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“…It is noteworthy that the stimulatory effect of PA on IL-6 expression in cardiac MIC ECs is cell type specific since PA failed to stimulate IL-6 expression in macrophages although it enhances the effect of LPS on IL-6 expression 32 . Furthermore, our time-course study as shown in Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Active sphingolipids play an important role in regulating expression of pro-inflammatory genes 32, 34 . Therefore, we sought to elucidate the interactions between LPS and PA on sphingolipid metabolism in human cardiac MIC ECs and determine if sphingolipids are involved in IL-6 upregulation by LPS and PA.…”

Section: Discussionmentioning

confidence: 99%

GPR40/FFA1 and neutral sphingomyelinase are involved in palmitate-boosted inflammatory response of microvascular endothelial cells to LPS

Jin

et al. 2015

Atherosclerosis

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Objectives Increased levels of both saturated fatty acids (SFAs) and lipopolysaccharide (LPS) are associated with type 2 diabetes. However, it remains largely unknown how SFAs interact with LPS to regulate inflammatory responses in microvascular endothelial cells (MIC ECs) that are critically involved in atherosclerosis as a diabetic complication. In this study, we compared the effects of LPS, palmitic acid (PA), the most abundant saturated fatty acid, or the combination of LPS and PA on interleukin (IL)-6 expression by MIC ECs and explored the underlying mechanisms. Methods Human cardiac MIC ECs were treated with LPS, PA and LPS plus PA and the regulatory pathways including receptors, signal transduction, transcription and post-transcription, and sphingolipid metabolism for IL-6 expression were investigated. Results G protein-coupled receptor (GPR)40 or free fatty acid receptor 1 (FFA1), but not toll-like receptor 4, was involved in PA-stimulated IL-6 expression. PA not only stimulated IL-6 expression by itself, but also remarkably enhanced LPS-stimulated IL-6 expression via a cooperative stimulation on mitogen-activated protein kinase and nuclear factor kappa B signaling pathways, and both transcriptional and post-transcriptional activation. Furthermore, PA induced a robust neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis that was involved in PA-augmented IL-6 upregulation. Conclusion PA boosted inflammatory response of microvascular endothelial cells to LPS via GPR40 and nSMase.

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“…CER has a wide range of biological functions in cellular signaling such as activating protein kinase C and c-Jun N-terminal kinase (JNK), induction of β-cell apoptosis and insulin resistance [61, 62]. CER increases reactive oxidizing species and activates the NF-κB pathway, which induces pro-inflammatory cytokines, diabetes and insulin resistance [63]. CER is synthesized from serine and palmitoyl-CoA or hydrolysis of SM by acid sphingomyelinase (ASM).…”

Section: Discussionmentioning

confidence: 99%

Bile acid signaling in lipid metabolism: Metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice

Jiang

Cheng

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

173

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Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tg mice. Metabolomics analysis identified 13 metabolites in bile acid synthesis including taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-β-muricholic acid (T-β-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-β-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12α-hydroxylated bile acids and increasing intestinal T-β-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity.

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Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages

Abstract: Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages.

Cited by 79 publications

References 52 publications

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

GPR40/FFA1 and neutral sphingomyelinase are involved in palmitate-boosted inflammatory response of microvascular endothelial cells to LPS

Bile acid signaling in lipid metabolism: Metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice

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