Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo

Cui, Wei; Paglialunga, Sabina; Kalant, David; Lü, Huiling; Roy, Christian; Laplante, Mathieu; Deshaies, Yves; Cianflone, Katherine

doi:10.1152/ajpendo.00565.2006

Cited by 44 publications

(41 citation statements)

References 46 publications

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“…Further, additional studies with transfected cells indicated the ability of C5L2 to bind and transduce signals in response to C3a, C4a, and their des-arginine derivatives (9,11,36,37). Some of these discrepancies have subsequently been resolved (6,38).…”

Section: Discussionmentioning

confidence: 99%

The C5a Receptor (C5aR) C5L2 Is a Modulator of C5aR-mediated Signal Transduction

Bamberg

Mackay

Lee

et al. 2010

Journal of Biological Chemistry

226

284

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The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor (C5aR) and C5L2. C5aR is a classical G protein-coupled receptor, whereas C5L2 is structurally homologous but deficient in G protein coupling. In human neutrophils, we show C5L2 is predominantly intracellular, whereas C5aR is expressed on the plasma membrane. Confocal analysis shows internalized C5aR following ligand binding is co-localized with both C5L2 and ␤-arrestin. Antibody blockade of C5L2 results in a dramatic increase in C5a-mediated chemotaxis and ERK1/2 phosphorylation but does not alter C5a-mediated calcium mobilization, supporting its role in modulation of the ␤-arrestin pathway. Association of C5L2 with ␤-arrestin is confirmed by cellular co-immunoprecipitation assays. C5L2 blockade also has no effect on ligand uptake or C5aR endocytosis in human polymorphonuclear leukocytes, distinguishing its role from that of a rapid recycling or scavenging receptor in this cell type. This is thus the first example of a naturally occurring seven-transmembrane segment receptor that is both obligately uncoupled from G proteins and a negative modulator of signal transduction through the ␤-arrestin pathway. Physiologically, these properties provide the possibility for additional fine-tuning of host defense.The complement anaphylatoxin C5a is one of the most potent inflammatory mediators of the innate immune system, with the ability to activate all classes of myeloid cells as well as cells of many other lineages. Multiple studies using experimental animals deficient in C5 or mice with targeted deletion of the C5a receptor (C5aR) 4 have demonstrated the critical role for this anaphylatoxin in host defense. Generation of C5a has also been associated with disease conditions, including asthma, contact sensitivity reactions, autoimmune arthritis, and sepsis (reviewed in Refs. 1-3). C5a manifests its activities by interaction with two known receptors, C5aR and C5L2. Cellular stimulation of the C5aR through G␣ i2 , G␣ i3 , or G␣ 16 results in intracellular calcium mobilization and activation of signaling pathways including phosphatidylinositol 3-kinase, diacylglycerol, MAPK, ERK, and others (4, 5), (reviewed in Ref. 6).Like the C5aR, C5L2 is a putative seven-transmembrane segment protein that was identified by Ohno et al. (7) as a cDNA with homology to the C5aR. It has similar sequence homology with the formyl peptide receptor (FPR) and the chemokine receptor chemR23. C5L2 is expressed on neutrophils, macrophages, and immature dendritic cells in coordination with the C5aR, although its mRNA is present at significantly reduced levels (7,8). Expression has additionally been reported in adrenal gland, spinal cord, thyroid, liver, lung, spleen, brain, and heart (9, 10).Studies of the distinct properties of C5L2-utilizing transfection systems demonstrate its ability to bind C5a with affinity similar to that of the C5aR. It binds the metabolite des-Arg C5a with higher avidity (11,12). In con...

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Section: Discussionmentioning

confidence: 99%

The C5a Receptor (C5aR) C5L2 Is a Modulator of C5aR-mediated Signal Transduction

Bamberg

Mackay

Lee

et al. 2010

Journal of Biological Chemistry

226

284

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“…Modulation of ligand binding. While a number of blocking antibodies specific for the mouse, rat, or human C5a 2 receptor have been developed and employed by different investigators in vitro and in vivo (Gao et al, 2005;Cui et al, 2007;Lee et al, 2008;Bamberg et al, 2010), to our knowledge the only antagonists for the human C5a 2 receptor are the C5a mutant jun/fos-A8, and its derivative jun/fos-A8 D71-73 , which inhibit ligand binding to both the C5a 1 receptor and C5a 2 receptor (Heller et al, 1999;Otto et al, 2004).…”

Section: A Introductionmentioning

confidence: 99%

“…Thus, the ASP/C5a 2 receptor neutralizing antibodies that effectively block the ASP-C5a 2 receptor interaction altered lipid distribution and energy utilization. Moreover, continuous administration of anti-ASP antibodies as compared with an IgG negative control had effects on energy expenditure and glucose storage, increasing in vivo whole-body energy utilization (Cui et al, 2007;Paglialunga et al, 2010).…”

mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

Klos

Wende²,

Wareham³

et al. 2013

Pharmacol Rev

232

245

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“…Activation and phosphorylation of C5L2 leads to increased fatty acid uptake, increased glucose transport, and stimulation of diacylglycerol acyltransferase activity (9,10,19,20). ASP is produced through cleavage of the precursor protein complement C3 via factor B and adipsin (factor D) interaction generating C3a, which is rapidly desarginated to produce ASP (also known as C3adesArg) (6, 25).…”

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confidence: 99%

Acute injection of ASP in the third ventricle inhibits food intake and locomotor activity in rats

Roy

Gauvreau

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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ing protein (ASP; also known as C3adesArg) stimulates triglyceride synthesis and glucose transport via interaction with its receptor C5L2, which is expressed peripherally (adipose tissue, muscle) and centrally. Previous studies have shown that ASP-deficient mice (C3KO) and C5L2-deficient mice (C5L2KO) are hyperphagic (59 to 229% increase, P Ͻ 0.0001), which is counterbalanced by increased energy expenditure measured as oxygen consumption (V O2) and a lower RQ. The aim of the present study was to evaluate ASP's effect on food intake, energy expenditure, and neuropeptide expression. Male rats were surgically implanted with intracerebroventricular (icv) cannulas directed toward the third ventricle. After a 5-h fast, rats were injected, and food intake was assessed at 0.5, 1, 2, 4, 16, 24, and 48 h, with a 5-to 7-day washout period between each injection. Acute icv injections of ASP (0.3-1,065 pmol) had a time-dependent effect on decreasing food intake by 20 to 57% (P Ͻ 0.05). Decreases were detected by 30 min (maximum 57%, P Ͻ 0.01) and at the highest dose effects extended to 48 h (19%, P Ͻ 0.05, 24-to 48-h period). Daily body weight gain was decreased by 131% over the first 24 h and 29% over the second 24 h (P Ͻ 0.05). A conditioned taste aversion test indicated that there was no malaise. Furthermore, acute ASP injection affected energy substrate usage, demonstrated by decreased V O2 and RQ (P Ͻ 0.05; implicating greater fatty acid usage), with a 49% decrease in total activity over 24 h (P Ͻ 0.05). ASP administration also increased anorexic neuropeptide POMC expression (44%) in the arcuate nucleus, with no change in NPY. Altogether ASP may have central in addition to peripheral effects. acylation-stimulating protein; C5L2; energy metabolism; proopiomelanocortin IN RECENT YEARS, MUCH ATTENTION HAS FOCUSED on the hypothalamic-adipose axis (46). White adipose tissue (WAT), recognized originally for its capacity to store excess dietary energy in the form of triglycerides (TG), is now considered an endocrine organ because of its capacity to secrete hormones and cytokines (17). WAT is now recognized as a fundamental participant in the control of energy metabolism (22). The number of adipokines has expanded rapidly, and these include leptin, adiponectin, resistin, acylation-stimulating protein (ASP), and many more (17). The role of ASP and its involvement in the control of energy balance and in the development of obesity have been actively studied in our group for the last decade.ASP promotes TG synthesis in WAT through interaction with its cell surface receptor C5L2. Activation and phosphorylation of C5L2 leads to increased fatty acid uptake, increased glucose transport, and stimulation of diacylglycerol acyltransferase activity (9,10,19,20). ASP is produced through cleavage of the precursor protein complement C3 via factor B and adipsin (factor D) interaction generating C3a, which is rapidly desarginated to produce ASP (also known as C3adesArg) (6, 25). C3-knockout mice (C3 Ϫ/Ϫ ; also known as C3KO) are deficient in AS...

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Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo

Cited by 44 publications

References 46 publications

The C5a Receptor (C5aR) C5L2 Is a Modulator of C5aR-mediated Signal Transduction

The C5a Receptor (C5aR) C5L2 Is a Modulator of C5aR-mediated Signal Transduction

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

Acute injection of ASP in the third ventricle inhibits food intake and locomotor activity in rats

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