Targeting the signaling pathway of acylation stimulating protein

Acylation stimulating protein (ASP; C3adesArg) stimulates triglyceride synthesis (TGS) and glucose transport in preadipocytes/adipocytes through C5L2, a G-protein-coupled receptor. Here, ASP signaling is compared with insulin in 3T3-L1 cells. ASP stimulation is not Gαs or Gαi mediated (pertussis and cholera toxin insensitive), suggesting Gαq as a candidate. Phospholipase C (PLC) is required, because the Ca2+ chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester and the PLC inhibitor U73122 decreased ASP stimulation of TGS by 93.1% (P < 0.0.001) and 86.1% (P < 0.004), respectively. Wortmannin and LY294002 blocked ASP effect by 69% (P < 0.001) and 116.1% (P < 0.003), respectively, supporting phosphatidylinositol 3-kinase (PI3K) involvement. ASP induced rapid, transient Akt phosphorylation (maximal, 5 min; basal, 45 min), which was blocked by Akt inhibition, resembling treatment by insulin. Downstream of PI3K, mamalian target of rapaycin (mTOR) is required for insulin but not ASP action. By contrast, both ASP and insulin activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2) pathway, with rapid, pronounced increases in ERK1/2 phosphorylation, effects partially blocked by PD98059 (64.7% and 65.9% inhibition, respectively; P < 0.001). Time-dependent (maximal, 30 min) transient calcium-dependent phospholipase A2 (cPLA2)-Ser505 phosphorylation (by MAPK/ERK1/2) was demonstrated by Western blot analysis. ASP signaling involves sequential activation of PI3K and PLC, with downstream activation of protein kinase C, Akt, MAPK/ERK1/2, and cPLA2, all of which leads to an effective and prolonged stimulation of TGS. Acylation stimulating protein (ASP; C3adesArg) stimulates triglyceride synthesis (TGS) and glucose transport in preadipocytes/adipocytes through C5L2, a G-protein-coupled receptor. Here, ASP signaling is compared with insulin in 3T3-L1 cells. ASP stimulation is not Gαs or Gαi mediated (pertussis and cholera toxin insensitive), suggesting Gαq as a candidate. Phospholipase C (PLC) is required, because the Ca2+ chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester and the PLC inhibitor U73122 decreased ASP stimulation of TGS by 93.1% (P < 0.0.001) and 86.1% (P < 0.004), respectively. Wortmannin and LY294002 blocked ASP effect by 69% (P < 0.001) and 116.1% (P < 0.003), respectively, supporting phosphatidylinositol 3-kinase (PI3K) involvement. ASP induced rapid, transient Akt phosphorylation (maximal, 5 min; basal, 45 min), which was blocked by Akt inhibition, resembling treatment by insulin. Downstream of PI3K, mamalian target of rapaycin (mTOR) is required for insulin but not ASP action. By contrast, both ASP and insulin activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2) pathway, with rapid, pronounced increases in ERK1/2 phosphorylation, effects partially blocked by PD98059 (64.7% and 65.9% inhibition, respectively; P < 0.001). Time-dependent (maximal, 30 min) transient calcium-dependent phospholipase A2 (cPLA2)-Ser505 phosphorylation (by MAPK/ERK1/2) was demonstrated by Western blot analysis. ASP signaling involves sequential activation of PI3K and PLC, with downstream activation of protein kinase C, Akt, MAPK/ERK1/2, and cPLA2, all of which leads to an effective and prolonged stimulation of TGS. Obesity is one of the most common health problems of our society (1Rossner S. Obesity: the disease of the twenty-first century.Int. J. Obes. Relat. Metab. Disord. 2002; 26: 2-4Google Scholar), and our biggest challenge is understanding how to limit its progress. Adipose tissue provides a long-term storage reservoir for energy surplus in the form of triglycerides (lipogenesis), which in turn can be mobilized (lipolysis) when necessary to provide energy for essential cellular processes (2Large V. Peroni O. Letexier D. Ray H. Beylot M. Metabolism of lipids in human white adipocyte.Diabetes Metab. 2004; 30: 294-309Google Scholar). Normally, the balance between lipogenesis and lipolysis is tightly controlled by numerous hormonal components. Predominance of the lipogenic state, whether driven by increases in food intake or lack of exercise, is dependent on the activation of specific intracellular enzymatic pathways. Regrettably, the continuous augmentation of adipose tissue stores leads to obesity, which, in turn, can lead to a number of metabolic perturbations, such as diabetes, coronary artery disease, and hypertension. In addition to being a storage organ, adipose tissue produces a variety of adipokines, some of which are closely involved in adipose tissue metabolism in an autocrine and paracrine manner (for review, see 3Guerre-Millo M. Adipose tissue hormones.J. Endocrinol. Invest. 2002; 25: 855-861Google Scholar). Acylation Stimulating Protein (ASP) is generated by adipose tissue through the interaction of Factor B and adipsin with complement C3 and is identical to C3adesArg (4Baldo A. Sniderman A.D. St-Luce S. Avramoglu R.K. Maslowska M. Hoang B. Monge J.C. Bell A. Mulay S. Cianflone K. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis.J. Clin. Invest. 1993; 92: 1543-1547Google Scholar). ASP production, along with its precursor proteins Factor B, adipsin, and C3, is increased during the differentiation of human and mouse adipocytes (5Cianflone K. Maslowska M. Differentiation induced production of ASP in human adipocytes.Eur. J. Clin. Invest. 1995; 25: 817-825Google Scholar, 6Peake P.W. O'Grady S. Pussell B.A. Charlesworth J.A. Detection and quantification of the control proteins of the alternative pathway of complement in 3T3-L1 adipocytes.Eur. J. Clin. Invest. 1997; 27: 922-927Google Scholar), a production that can be further augmented by insulin and dietary chylomicrons (7Maslowska M. Scantlebury T. Germinario R. Cianflone K. Acute in vitro production of ASP in differentiated adipocytes.J. Lipid Res. 1997; 38: 21-31Google Scholar). In vivo production of ASP in the adipose environment has been elegantly demonstrated by studying arterial-venous differences across an adipose tissue bed (8Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.J. Lipid Res. 1998; 39: 884-891Google Scholar, 9Kalant D. Phelis S. Fielding B.A. Frayn K.N. Cianflone K. Sniderman A.D. Increased postprandial fatty acid trapping in subcutaneous adipose tissue in obese women.J. Lipid Res. 2000; 41: 1963-1968Google Scholar). Local adipose ASP production increased postprandially and correlated with plasma triglyceride (TG) clearance. This correlation of ASP with postprandial TG clearance has been demonstrated across a wide range of fasting ASP levels in men and woman (10Cianflone K. Zakarian R. Couillard C. Delplanque B. Despres J.P. Sniderman A.D. Fasting acylation stimulating protein is predictive of postprandial triglyceride clearance.J. Lipid Res. 2004; 45: 124-131Google Scholar). Moreover, the circulating levels of ASP are increased in obesity, with greater increases observed in women than in men (11Maslowska M. Vu H. Phelis S. Sniderman A.D. Rhode B.M. Blank D. Cianflone K. Plasma acylation stimulating protein, adipsin and lipids in non-obese and obese populations.Eur. J. Clin. Invest. 1999; 29: 679-686Google Scholar). Upon weight loss, ASP levels return to normal (12Cianflone K. Sniderman A.D. Kalant D. Marliss E.B. Gougeon R. Response of plasma ASP to a prolonged fast.Int. J. Obes. 1995; 19: 604-609Google Scholar, 13Sniderman A.D. Cianflone K. Eckel R.H. Levels of Acylation Stimulating Protein in obese women before and after moderate weight loss.Int. J. Obes. 1991; 15: 333-336Google Scholar, 14Faraj M. Havel P.J. Phelis S. Blank D. Sniderman A.D. Cianflone K. Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects.J. Clin. Endocrinol. Metab. 2003; 88: 1594-1602Google Scholar). Studies have shown that ASP levels are also significantly higher in diabetes and cardiovascular disease (15Cianflone K. Xia Z. Chen L.Y. Critical review of Acylation Stimulating Protein physiology in humans and rodents.Biochim. Biophys. Acta. 2003; 1609: 127-143Google Scholar). ASP plays a key role in the regulation of lipid storage in that it stimulates the esterification of fatty acids onto a glycerol backbone, resulting in the augmentation of intracellular triglyceride depots in human preadipocytes, adipocytes, and skin fibroblasts (16Cianflone K. Maslowska M. Sniderman A.D. Acylation stimulating protein (ASP), an adipocyte autocrine: new directions.Semin. Cell Dev. Biol. 1999; 10: 31-41Google Scholar, 17Cianflone K. The Acylation Stimulating Protein pathway: clinical implications.Clin. Biochem. 1997; 30: 301-312Google Scholar). In stimulating triglyceride synthesis (TGS), ASP increases the activity of diacylglycerol acyltransferase (DGAT; the final enzyme in TGS) in membrane preparations from adipocytes (18Yasruel Z. Cianflone K. Sniderman A.D. Rosenbloom M. Walsh M. Rodriguez M.A. Effect of acylation stimulating protein on the triacylglycerol synthetic pathway of human adipose tissue.Lipids. 1991; 26: 495-499Google Scholar). ASP stimulates glucose transport in both adipocyte and muscle cells (19Maslowska M. Sniderman A.D. Germinario R. Cianflone K. ASP stimulates glucose transport in cultured human adipocytes.Int. J. Obes. Relat. Metab. Disord. 1997; 21: 261-266Google Scholar, 20Tao Y. Cianflone K. Sniderman A.D. Colby-Germinario S.P. Germinario R.J. Acylation-stimulating protein (ASP) regulates glucose transport in the rat L6 muscle cell line.Biochim. Biophys. Acta. 1997; 1344: 221-229Google Scholar) through the translocation of the glucose transporters GLUT1, GLUT4, and GLUT3 (21Germinario R. Sniderman A.D. Manuel S. Pratt S. Baldo A. Cianflone K. Coordinate regulation of triacylglycerol synthesis and glucose transport by Acylation Stimulating Protein.Metabolism. 1993; 42: 574-580Google Scholar). Finally, as with insulin, ASP also inhibits lipolysis (22Van Harmelen V. Reynisdottir S. Cianflone K. Degerman E. Hoffstedt J. Nilsell K. Sniderman A. Arner P. Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation-stimulating protein and insulin.J. Biol. 1999; Scholar), the effects of ASP and insulin are C5L2, an was as an ASP D. Maslowska M. Sniderman A.D. Cianflone K. The protein the Biol. 2003; Scholar, D. R. R. Cianflone K. is a for acylation-stimulating Biol. Scholar). is a to the and of In cells with the ASP with and cells to ASP not for TGS and glucose transport D. R. R. Cianflone K. is a for acylation-stimulating Biol. Scholar). how ASP with the to a is not on ASP signaling demonstrated the of protein kinase C in TGS A. Sniderman A.D. S. Cianflone K. pathway of acylation stimulating of protein kinase Lipid Res. 1995; Scholar). numerous have on the signaling of the insulin pathway glucose transport and the of the signaling resulting in the stimulation of TGS are The of was to the signaling pathway for ASP stimulation of TGS compared with insulin. 3T3-L1 as a cell the of the phospholipase C phosphatidylinositol 3-kinase Akt, and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2) pathways. 3T3-L1 from the tissue such as and from toxin Akt 1,2-bis(o-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester LY294002 and U73122 of insulin, and from was from from and tissue from was from for protein was from ASP was isolated and from human plasma as (4Baldo A. Sniderman A.D. St-Luce S. Avramoglu R.K. Maslowska M. Hoang B. Monge J.C. Bell A. Mulay S. Cianflone K. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis.J. Clin. Invest. 1993; 92: 1543-1547Google Scholar). was for by the The activity of ASP was by its to TGS in 3T3-L1 3T3-L1 preadipocytes, in with TGS was as in (16Cianflone K. Maslowska M. Sniderman A.D. Acylation stimulating protein (ASP), an adipocyte autocrine: new directions.Semin. Cell Dev. Biol. 1999; 10: 31-41Google Scholar, 17Cianflone K. The Acylation Stimulating Protein pathway: clinical implications.Clin. Biochem. 1997; 30: 301-312Google Scholar). the cells on for the after cell to for by with for 30 or or the was to with specific and insulin, or and to the and from in TGS was in the of and in the was and the cells in The lipids for in of and with an of the Lipid to in a and in of and lipids by in acid with lipids lipids with and the to triglyceride and by Cell proteins in for and by the of and for the of of protein the of Biochem. Scholar). because TGS and lipolysis are TGS. during the not TGS was cell protein, which of the with the in diacylglycerol and free fatty acids TGS stimulation with ASP was to that with insulin was to and that with was to was as to on in for and with ASP or insulin in for and The was and of and was to the for with cell and to for of the for further analysis. with the Western blot was to the of cell and the for of cell was and the proteins by to a membrane and with the to of intracellular proteins and with the to the proteins in The proteins with the from The to TGS in as and are as by for treatment and treatment with the with P < Western with the system was to the of the Gαi in ASP action. 3T3-L1 for with before stimulation with ASP or insulin. shown in not TGS is as ASP stimulation of TGS is by treatment for ASP for ASP is P also stimulates TGS in 3T3-L1 C. Germinario R.J. The effects of on and lipid insulin and Lipid Res. 2003; Scholar) through the insulin which to the of kinase effect on the TGS of insulin for insulin for insulin P the increases in intracellular and translocation by ASP A. Sniderman A.D. S. Cianflone K. pathway of acylation stimulating of protein kinase Lipid Res. 1995; Scholar) are of PLC in ASP signaling Y. signaling by of and activation of protein kinase Scholar). This was specific and Ca2+ The effect of a and inhibitor of PLC J.A. U73122 inhibits Ca2+ in to and but not to in rat Biol. Scholar), was shown in U73122 in a but in TGS the P < 0.001). The ASP effect was blocked in a to a loss of ASP activity the (P < the TGS P < was by U73122 not that both ASP and insulin can in to insulin, its effects The is a that and the cell as an intracellular Ca2+ shown in TGS decreased but significantly with P < 0.001). TGS P < 0.001) was significantly by and 93.1% and respectively; P < 0.001). insulin TGS by an effect that was by and with 5 and (P < compared with insulin The of in ASP signaling was a which as an for of acid M. M. Phospholipase and cell of a J. 2000; Scholar). the generated can be to by the enzyme acid In the of TGS was was as P < the ASP effect was not The of PI3K was the and LY294002 the of PI3K and have been to the role of PI3K in insulin on glucose transport J. K. J. of 3-kinase and in triacylglycerol synthesis in 1999; Scholar, P.W. K. M. of the translocation of and in 3T3-L1 cells by the phosphatidylinositol 3-kinase J. Scholar). shown in effect on TGS. The ASP effect for ASP P < was by to for ASP P < was all Wortmannin also to of the TGS for insulin for insulin P < with LY294002 TGS P < 0.001) was in a manner to TGS levels LY294002 (P < ASP effect was observed on was observed with LY294002 (P < 0.001). of TGS with of LY294002 was compared with for and TGS. PI3K can the activation of protein and Western blot that phosphorylation on from to after ASP or insulin stimulation not the Akt, the target of is on an necessary for shown in phosphorylation of Akt on by ASP is rapid, its between 5 and and to levels by 45 activation of Akt phosphorylation was as min), but Akt the with a treatment of cells with the Akt inhibitor in the of ASP stimulation in a manner (P < TGS was the of inhibitor P < have shown that is in ASP signaling and that a also stimulates TGS A. Sniderman A.D. S. Cianflone K. pathway of acylation stimulating of protein kinase Lipid Res. 1995; Scholar). is through phosphorylation of the by A. of protein kinase C by kinase Biol. 1998; Scholar) and activation by Ca2+ and 3T3-L1 with TGS and and LY294002 both the ASP and insulin effects the TGS of was by LY294002 P treatment not Akt phosphorylation not suggesting that downstream of PI3K as a of TGS. the intracellular with decreased stimulation of TGS from to an of P < of on stimulation of inhibitor inhibitor and 1,2-bis(o-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) triglyceride cells with the the for 30 and with for an the TGS was as of The to TGS in of the and are as TGS addition and was as The of was in the for of the The by the inhibitor inhibitor and in a new 1,2-bis(o-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) triglyceride cells with the the for 30 and with for an the TGS was as of The to TGS in of the and are as TGS addition and was as The of was in the for of the The by the The mamalian target of rapaycin (mTOR) pathway, which involves the activation of kinase and protein is a downstream target of PI3K through the pathway specific inhibitor of and kinase not ASP TGS activity that the TGS activity was also by By contrast, the stimulation of TGS was significantly in the of and 5 and (P < 0.001). which the activation of kinase but not that of significantly TGS P < 0.001). ASP stimulation of TGS was also the observed for and ASP stimulation all By contrast, TGS was with stimulation the (P < 0.001). In Western blot of kinase phosphorylation for ASP or insulin not that not in the signaling pathway for TGS. PI3K and activation can lead to the activation of glucose in 3T3-L1 J. Endocrinol. Metab. 2004; Scholar, R. H. H. D. Protein kinase C by 1993; Scholar). shown in a TGS was but of both and TGS was observed all (P < for both ASP and with stimulation stimulation of TGS was also decreased for for P < ASP ERK1/2 was by an effect also with insulin activation as as activation can lead to the activation of acid and an inhibitor of G-protein-coupled J. activation of phospholipase A2 and acid release in Scholar), effect on the effect of ASP which significantly increased (P < 0.001). TGS levels of The of calcium-dependent phospholipase A2 was the inhibitor R. of phospholipase A2 but not phospholipase A2 release of free in human Biol. Scholar). of significantly and TGS TGS was the by was pronounced on and with of the ASP effect and of the insulin Western blot with to by a phosphorylation of was a effect 30 the of can as a signaling or can be as a precursor for the production of inhibitor was to ASP and insulin TGS by and (P < respectively, with of TGS with of the not on the and the of Baldo A. Sniderman A.D. S. Cianflone K. pathway of acylation stimulating of protein kinase Lipid Res. 1995; Scholar), a for the ASP intracellular signaling pathway is in The ASP C5L2, to a of G-protein-coupled that and the M. T. M. T. H. C5L2, is in and but not in 2000; Scholar). the and signaling are mediated through Gαi and are M. K. A. and are for human cells and through a Scholar, J. O. A. A. A. J. T. and to but not to with a transient release of a J. 1997; 27: Scholar). and to in the activation of by the M. T. M. T. H. C5L2, is in and but not in 2000; Scholar, of the between protein and phospholipase 1999; 38: Scholar). to ASP and the have demonstrated that Gαs was not was by ASP in TGS A. Sniderman A.D. S. Cianflone K. pathway of acylation stimulating of protein kinase Lipid Res. 1995; Scholar). In have also in with that to Gαi The has for complement and Biol. 2002; Scholar), the ASP activation of from that of in the on and on This a of ASP and Gαq or the from the which leads to PLC and PI3K PLC activation in through the Gαq or D. D. of the activate phospholipase C Biol. Scholar) in the release of and stimulates the release of intracellular Ca2+ from the which further as a signaling a number of intracellular PI3K, Akt, and Z. protein kinase C the of differentiation by 1995; Scholar, activation of Akt regulates of mouse Biol. 2004; Scholar, of of phospholipase a and a Biol. Scholar). of are involved in the ASP pathway the effective by Ca2+ of the ASP signaling The that of the ASP effect was observed that and PI3K is involved in ASP TGS B. by of Cell Res. 1999; Scholar). the PI3K, is the G-protein-coupled by the S. the between the of the 3-kinase and role in the activation of enzyme by Biol. 1999; Scholar, A. H. M. J. M. K. P. of a PI3K is dependent a tightly 1997; Scholar), which leads to activation in turn, it the A. of protein kinase C by kinase Biol. 1998; Scholar). is a of and demonstrated that ASP treatment leads to transient increases in min) as as a prolonged in intracellular A. Sniderman A.D. S. Cianflone K. pathway of acylation stimulating of protein kinase Lipid Res. 1995; Scholar). The in is with increased intracellular activity and translocation to the membrane A. Sniderman A.D. S. Cianflone K. pathway of acylation stimulating of protein kinase Lipid Res. 1995; Scholar). activation by C. R. The role of protein kinase C, and protein kinase in hormonal stimulation of phospholipase in rat Biol. Scholar) has been shown to a prolonged in intracellular have the of in and PI3K activation lead to phosphorylation glucose in 3T3-L1 J. Endocrinol. Metab. 2004; Scholar, R. H. H. D. Protein kinase C by 1993; Scholar). PI3K and PLC are to be in activation of both to be because of one or the in the of TGS. that after ASP the PI3K pathway as as the pathway with the is by increases in intracellular membrane which stimulates phosphorylation of and regulation of phospholipase Biol. 1997; Scholar, M. Y. of phospholipase A2 by a mitogen-activated protein phosphorylation pathway in Biol. 1995; Scholar, S.P. J.A. mitogen-activated protein kinase phospholipase A2 in that phosphorylation is not required for of acid by Biol. Scholar). ASP signaling involves the and transient phosphorylation of ERK1/2 which leads to phosphorylation effects 30 the with and the of phosphorylation are to observed for a that PLC activation 3-kinase regulates phospholipase A2 activity and in muscle Biochem. Biophys. 2002; Scholar) and has been shown to TGS C. R. Differentiation of paracrine role of stimulation of adipose cells by Scholar, P. C. R. as a of white adipose stimulation of adipose cell Scholar). acid can activity T. Y. M. K. Y. of diacylglycerol and fatty acid for protein kinase C its 1991; 88: Scholar) as as the translocation of glucose transporters C. J.P. S. acid stimulates glucose in 3T3-L1 adipocytes by and levels the plasma for of and Biol. Scholar) and by glucose transport the This also provides the regulation of TGS by insulin. PI3K, Akt, and all shown to be in the insulin stimulation of TGS. of glucose intracellular has been in 3T3-L1 adipocytes J.P. J.C. S. S. The role of Ca2+ in glucose transport in 3T3-L1 Biol. Scholar, B. K. M. D. The of an range of free for glucose transport in rat adipocytes.J. Biol. Scholar, L.Y. of on glucose transport in isolated rat 1997; Scholar). In contrast, is the that intracellular inhibits TGS in 3T3-L1 are a number of in the ASP and insulin signaling are a number of differences as PLC is involved in ASP signaling but is not involved in insulin stimulation of TGS as shown in glucose transport for the of a phospholipase kinase C signaling pathway in insulin glucose transport in 2003; Scholar, J. phospholipase a kinase dependent in 3T3-L1 Biophys. Res. Scholar). the pathway is for it is not involved in ASP differences in ASP and insulin a of signaling for ASP and insulin. Downstream of Akt can how PLC, PI3K, MAPK/ERK1/2, and activation lead to increased TGS. have demonstrated that ASP increases glucose transport as as fatty acid esterification onto the glycerol through the activation of enzyme that is specific to TGS) (18Yasruel Z. Cianflone K. Sniderman A.D. Rosenbloom M. Walsh M. Rodriguez M.A. Effect of acylation stimulating protein on the triacylglycerol synthetic pathway of human adipose tissue.Lipids. 1991; 26: 495-499Google Scholar, S. E. S. C. of a an a key enzyme in triacylglycerol 1998; Scholar) but not synthesis D. R. R. Cianflone K. is a for acylation-stimulating Biol. Scholar). ASP effects on TGS and glucose transport to be because ASP stimulates glucose transport in the of and glucose is not required for ASP stimulation of because of or in the can be for the D. R. R. Cianflone K. is a for acylation-stimulating Biol. Scholar). both effects are required for ASP stimulation of TGS. to glucose it has been demonstrated that PI3K and activation lead to the translocation of glucose and ASP pathway for the of a phospholipase kinase C signaling pathway in insulin glucose transport in 2003; Scholar, C. of 3-kinase to in 3T3-L1 adipocytes.J. Biol. 1998; Scholar). have been and S. E. S. C. of a an a key enzyme in triacylglycerol 1998; Scholar, S. P. E. B. T. of a diacylglycerol and Biol. Scholar), but is on on and with and S. P. E. B. T. of a diacylglycerol and Biol. Scholar, S. from the of diacylglycerol 2000; Scholar), it is to that enzyme be through In downstream of the activation of a to the activation of that to be have demonstrated that the ASP signaling pathway involves PI3K, PLC, MAPK/ERK1/2, and to TGS in a manner of that of insulin. This was by a from the for to a in Adipose

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.