A Novel Perspective on the ApoM-S1P Axis, Highlighting the Metabolism of ApoM and Its Role in Liver Fibrosis and Neuroinflammation

Hajny, Stefan; Christoffersen, Christina

doi:10.3390/ijms18081636

Cited by 23 publications

(20 citation statements)

References 148 publications

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“…We compared the expression of proangiogenic factors, which was upregulated by albumin-bound S1P stimulation as described above, in the presence of 1 μM ApoM with albumin-bound S1P. ApoM is a member of the Lipocalin family, which has a calyx-like pocket binding to S1P [ 37 ]. ApoM is secreted by hepatocytes and stored in the blood plasma.…”

Section: Resultsmentioning

confidence: 99%

“…Several reports have suggested different mechanisms between ApoM-bound S1P and albumin-bound S1P [ 37 ]. Ruiz et al demonstrated that ApoM-bound S1P restrained the TNF-α-induced expression of adhesion molecules (E-selectin, intercellular adhesion molecule-1, and vascular adhesion molecule-1) in primary human aortic endothelial cells (HAECs) [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein M Inhibits Angiogenic and Inflammatory Response by Sphingosine 1-Phosphate on Retinal Pigment Epithelium Cells

Terao

Honjo

Aihara

2017

IJMS

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Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammatory responses and proangiogenic factors. It has been suggested that S1P upregulates choroidal neovascularization (CNV) and may be deeply involved in the pathogenesis of exudative age-related macular degeneration (AMD). Recent studies have suggested that apolipoprotein M (ApoM), a carrier protein for S1P, modulates the biological properties of S1P in the pathogenesis of atherosclerosis. However, the role of ApoM/S1P in AMD has not been explored. We investigated the effect of S1P on proangiogenic factors in human retinal pigment epithelium (RPE) cell lines in vitro. S1P promoted the expression of vascular endothelial growth factor in RPE cells. Hypoxia inducible factor-1α expression was also upregulated. These S1P-induced enhancements in growth factors and chemotactic cytokines in RPE cells were significantly inhibited by ApoM treatment. Additionally, in vivo experiments using a laser-induced CNV murine model demonstrated that intravitreal ApoM injection significantly reduced the progression of CNV formation. Although the detailed mechanisms remain to be elucidated, the present results provide a novel potential therapeutic target for AMD, and demonstrate a suppressive role for ApoM and S1P in the pathology of CNV progression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Apolipoprotein M Inhibits Angiogenic and Inflammatory Response by Sphingosine 1-Phosphate on Retinal Pigment Epithelium Cells

Terao

Honjo

Aihara

2017

IJMS

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“…A published study showed significantly reduced sphinogsine-1P levels in the plasma of older Tangier subjects with very low levels of HDL and apoAI (99% and 97% reduction, respectively) (43). It is known that sphinogsine-1P transport to plasma involves apoM and spinster 2 and resides mainly on HDL 3 (6,(44)(45)(46). Longitudinal, prospective studies in larger cohorts are needed to determine plasma apoM, sphingoid bases, and their phosphate levels in Tangier subjects.…”

Section: Sphingoid Bases and Their Phosphatesmentioning

confidence: 99%

ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma

Iqbal

Walsh

Hammad

et al. 2018

Journal of Lipid Research

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Low density apoB-containing lipoproteins (B-lps) andHDLs carry the bulk of lipids in the blood circulation. These lipoproteins carry triacylglycerols, phospholipids, cholesterol, and sphingolipids (1-5). The major sphingolipids in the plasma are SM, ceramide (Cer), hexosylceramide (HxCer), and lactosylceramide (LactCer). Sphingolipids consist of a common 18-carbon amino-alcohol backbone, sphingosine. These molecules are structurally diverse and regulate significant physiologic functions associated with several metabolic diseases such as insulin resistance, progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH), atherosclerosis, and coronary artery disease (6-13). Earlier, we showed that microsomal triglyceride transfer protein (MTP) is a critical determinant of plasma Cer levels and partially contributes to plasma SM by investigating sphingolipid concentrations in the plasma of MTP-deficient abetalipoproteinemia subjects as well as in liver-and intestine-specific MTP-deficient mice (14). MTP deficiency in humans and mice was associated with 80% reductions in plasma Cer levels and 40% reduction in plasma SM levels. Mechanistic studies showed that MTP does not play a role in sphingolipid biosynthesis but is important for sphingolipid secretion. Furthermore, the data Abstract Sphingolipids, including ceramide, SM, and hexosylceramide (HxCer), are carried in the plasma by lipoproteins. They are possible markers of metabolic diseases, but little is known about their control. We previously showed that microsomal triglyceride transfer protein (MTP) is critical to determine plasma ceramide and SM, but not HxCer, levels. In human plasma and mouse models, we examined possible HxCer-modulating pathways, including the role of ABCA1 in determining sphingolipid plasma concentrations. Compared with control samples, plasma from patients with Tangier disease (deficient in ABCA1) had significantly lower HxCer (69%) and SM (40%) levels. Similarly, mice deficient in hepatic and intestinal ABCA1 had significantly reduced HxCer (79%) and SM (85%) levels. Tissue-specific ablation studies revealed that hepatic ABCA1 determines plasma HxCer and SM levels; that ablation of MTP and ABCA1 in the liver and intestine reduces plasma HxCer, SM, and ceramide levels; and that hepatic and intestinal MTP contribute to plasma ceramide levels, whereas only hepatic MTP modulates plasma SM levels. These results identify the contribution of ABCA1 to plasma SM and HxCer levels and suggest that MTP and ABCA1 are critical determinants of plasma sphingolipid levels.-Iqbal, J., M. T. Walsh, S. M. Hammad, M. Cuchel, D. J. Rader, and M. M. Hussain. ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma.

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“…Plasma apoM mainly associates with high-density lipoproteins (HDL) (more than 90%) and to a minor extent with low-density lipoproteins, very low-density lipoproteins, and chylomicrons [ 23 ]. HDL-associated apoM carries about 65% of plasma S1P, whereas albumin is able to transport approximately 30% of S1P [ 24 ]. As hepatocytes express and secrete the majority of circulating apoM, the liver plays a crucial role in maintaining the S1P gradient between blood and lymphoid tissues.…”

Section: Regulation Of Plasma S1p Content Via Liver-formed Apolipomentioning

confidence: 99%

Divergent Role of Sphingosine 1-Phosphate in Liver Health and Disease

Kleuser

2018

IJMS

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Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases.

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A Novel Perspective on the ApoM-S1P Axis, Highlighting the Metabolism of ApoM and Its Role in Liver Fibrosis and Neuroinflammation

Cited by 23 publications

References 148 publications

Apolipoprotein M Inhibits Angiogenic and Inflammatory Response by Sphingosine 1-Phosphate on Retinal Pigment Epithelium Cells

Apolipoprotein M Inhibits Angiogenic and Inflammatory Response by Sphingosine 1-Phosphate on Retinal Pigment Epithelium Cells

ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma

Divergent Role of Sphingosine 1-Phosphate in Liver Health and Disease

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