The apolipoprotein M/S1P axis controls triglyceride metabolism and brown fat activity

Christoffersen, Christina; Federspiel, Christine K.; Borup, Anna; Christensen, Peter Holdt; Madsen, André; Heine, Markus; Nielsen, Carsten H.; Kjær, Andreas; Holst, Birgitte; Heeren, Joerg; Nielsen, Lars Bo

doi:10.1016/j.atherosclerosis.2018.06.893

Cited by 6 publications

(15 citation statements)

References 35 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Fig. 1A S1), which is in accordance with the previous report (15). However, both male and female DKO mice did not exhibit discernible abnormalities in behavior and appeared healthy.…”

Section: Resultssupporting

confidence: 92%

“…DKO mice did not exhibit discernible abnormalities in behavior and appeared healthy. They showed smaller body size and increased lymphocytes, which were already observed in ApoM-single deficient mice (11,15). Interestingly, albumin deficiency alone had almost no effect on the concentration of plasma S1P (Fig.…”

mentioning

confidence: 54%

“…Whether this novel function of ApoA4 requires S1P action is not known. Because ApoM-bound S1P also exhibits anti-inflammatory and anti-atherogenic properties (14) as well as regulatory functions of glucose/ fat metabolism (15,44), it is possible that some of the proposed functions of ApoA4 might be exerted by its cargo S1P. 6.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Apolipoprotein A4 as a novel S1P chaperone 1913 bone marrow lymphopoiesis (11), liver function (12) and regeneration (13), restraint of inflammatory responses (14), brown adipocyte development (15), and control of blood pressure via NO release (16).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice

Obinata

Kuo

Wada

et al. 2019

Journal of Lipid Research

View full text Add to dashboard Cite

Sphingosine 1-phosphate (S1P) is a versatile lipid mediator essential for vascular development and lymphocyte trafficking. Five subtypes of cell-surface S1P receptors, S1PR1-5, mediate pleiotropic actions of extracellular S1P in multiple organ systems of vertebrates (1). In contrast to eicosanoid lipid mediators, which are produced upon stimulation and act transiently, S1P circulates tonically in blood and lymph at high (0.1-1 M) concentrations, which are significantly higher than the nanomolar concentrations required to activate S1P receptors. S1P in blood is produced primarily by red blood cells (RBCs) (2) and endothelial cells (3) and is secreted by specific S1P transporters, Mfsd2b (4) and Spns2 (5, 6), respectively. Due to its hydrophobic nature, S1P is poorly water soluble and requires carrier proteins for efficient transport and circulation. Most of plasma S1P (65%) is carried by HDL and the remainder by albumin (7). We have identified HDL-bound ApoM as a specific and physiologically relevant S1P chaperone (8), which is defined as a S1P carrier protein that facilitates specific receptor activation and biological responses. Structurally, ApoM belongs to the lipocalin family of proteins and accommodates S1P in an eight-stranded antiparallel  barrel structure. Most of the ApoM in plasma is anchored to HDL by its retained hydrophobic N-terminal signal peptide (9). Although ApoM is found only in 5% of total HDL particles, this subpopulation of HDL accounts for almost all of the lipoprotein-associated S1P (8). HDLbound S1P is important in vascular barrier function (8, 10), Abstract HDL-bound ApoM and albumin are protein chaperones for the circulating bioactive lipid, sphingosine 1-phosphate (S1P); in this role, they support essential extracellular S1P signaling functions in the vascular and immune systems. We previously showed that ApoM-and albumin-bound S1P exhibit differences in receptor activation and biological functions. Whether the physiological functions of S1P require chaperones is not clear. We examined ApoM-deficient, albumin-deficient, and double-KO (DKO) mice for circulatory S1P and its biological functions. In albumin-deficient mice, ApoM was upregulated, thus enabling S1P functions in embryonic development and postnatal adult life. The Apom:Alb DKO mice reproduced, were viable, and exhibited largely normal vascular and immune functions, which suggested sufficient extracellular S1P signaling. However, Apom:Alb DKO mice had reduced levels (25%) of plasma S1P, suggesting that novel S1P chaperones exist to mediate S1P functions. In this study, we report the identification of ApoA4 as a novel S1P binding protein. Recombinant ApoA4 bound to S1P, activated multiple S1P receptors, and promoted vascular endothelial barrier function, all reflective of its function as a S1P chaperone in the absence of ApoM and albumin. We suggest that multiple S1P chaperones evolved to support complex and essential extracellular signaling functions of this lysolipid mediator in a redundant manner.

show abstract

Section: Resultssupporting

confidence: 92%

mentioning

confidence: 54%

Section: Downloaded Frommentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice

Obinata

Kuo

Wada

et al. 2019

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…S1P is a signaling sphingolipid, also known as lysosphingolipid, which is a bioactive lipid mediator (11). It has been demonstrated in other studies that the binding of apo M and S1P has important implications in atherosclerosis (9), glucose tolerance (12), and insulin sensitivity (13). However, whether these effects are due to apo M itself or S1P, or other bioactive molecules carried by apo M, remains an important question to be studied.…”

mentioning

confidence: 99%

Editorial on Sramkova et al., “Apolipoprotein M: a novel adipokine decreasing with obesity and upregulated by calorie restriction”

Tso

2019

The American Journal of Clinical Nutrition

View full text Add to dashboard Cite

Propofol promotes migration, alleviates inflammation, and apoptosis of lipopolysaccharide‐induced human pulmonary microvascular endothelial cells by activating PI3K/AKT signaling pathway via upregulating APOM expression

Wang

Tang

2021

Drug Development Research

View full text Add to dashboard Cite

Propofol (PRO), a clinical potent intravenous anesthetic, plays a significant role in relieving inflammatory diseases by repressing the release of inflammatory cytokines. The present study was aimed to reveal a novel mechanism by which PRO alleviates acute lung injury (ALI). Lipopolysaccharide (LPS) was utilized to induce human pulmonary microvascular endothelial cells (HPMECs) so as to simulate the microenvironment of ALI, and the expression of apolipoprotein M (APOM) was examined with western blotting. Then, APOM was silenced and profopol was used to treat the LPS‐injured HPMECs. The cell viability, migration, and apoptosis were respectively observed after the processes of cell counting kit‐8, wound healing, transwell, and TUNEL assay. Meanwhile, the inflammatory response was detected by determining the contents of inflammatory cytokines. Subsequently, the relationship between phosphoinositide‐3 kinase (PI3K)/protein kinase B (AKT) signaling pathway and PRO was analyzed by western blotting. PI3K/AKT inhibitor LY294002 was employed to evaluate whether the effects of PRO on LPS‐challenged HPMECs injury were mediated by this pathway. Results revealed that APOM was notably downregulated in HPMECs after LPS exposure. PRO treatment promoted cell proliferation and migration while alleviated inflammation and apoptosis of LPS‐treated HPMECs, which was reversed by APOM‐downregulation. PRO brought about the upregulation of proteins in PI3K/AKT signaling pathway, and LY294002 intervention further accentuated the impacts of APOM‐knockdown on LPS‐challenged HPMECs injury. To conclude, PRO promotes migration and alleviates inflammation and apoptosis of LPS‐treated HPMECs by PI3K/AKT signaling pathway via upregulating APOM, which laid an experimental foundation for the future study and clinical application of PRO.

show abstract

The apolipoprotein M/S1P axis controls triglyceride metabolism and brown fat activity

Cited by 6 publications

References 35 publications

Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice

Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice

Editorial on Sramkova et al., “Apolipoprotein M: a novel adipokine decreasing with obesity and upregulated by calorie restriction”

Propofol promotes migration, alleviates inflammation, and apoptosis of lipopolysaccharide‐induced human pulmonary microvascular endothelial cells by activating PI3K/AKT signaling pathway via upregulating APOM expression

Contact Info

Product

Resources

About