Acylation Stimulating Protein Research Articles

Effects of sugar‐sweetened beverages on plasma acylation stimulating protein, leptin and adiponectin: Relationships with Metabolic Outcomes

ObjectiveWe determined the effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity.Design and Methods32 overweight/obese adults consumed glucose- or fructose-sweetened beverages (25% energy requirement) with their ad libitum diets for 8 weeks, followed by sweetened beverage consumption for 2 weeks with a standardized, energy-balanced diet. Plasma variables were measured at baseline, 2, 8 and 10 weeks, and body adiposity and insulin sensitivity at baseline and 10 weeks.ResultsFasting and postprandial ASP concentrations increased at 2 and/or 8 weeks. ASP increases correlated with changes in late-evening triglyceride concentrations. At 10 weeks, fasting adiponectin levels decreased in both groups, and decreases were inversely associated with baseline intra-abdominal fat volume. Sugar consumption increased fasting leptin concentrations; increases were associated with body weight changes. 24-h leptin profiles increased during glucose consumption and decreased during fructose consumption. These changes correlated with changes of 24-h insulin levels.ConclusionsThe consumption of fructose and glucose beverages induced changes in plasma concentrations of ASP, adiponectin and leptin. Further study is required to determine if these changes contribute to the metabolic dysfunction observed during fructose consumption.

Increased acylation stimulating protein levels in young obese males is correlated with systemic markers of oxidative stress

As little is known about relationship between acylation stimulating protein (ASP) and oxidative stress, whether there is any link between ASP and oxidative stress in young obese males were investigated. Forty-five obese (median body mass index (BMI) = 36.99 (IQR = 3.65) kg m(-2)) male subjects (median age = 22 (IQR = 6) years) and 24 age-matched (median age = 22.5 (IQR = 4.8) years) healthy male volunteers (median body mass index (BMI) = 23.67 (IQR = 2.45) kg m(-2)) were recruited into the study. All obese subjects have BMI > 30 kg m(-2), while all controls have BMI < 25 kg m(-2). Fasting plasma ASP, lipid hydroperoxide, high sensitivity C-reactive protein (hs-CRP), fasting insulin, triglyceride, LDL-cholesterol levels and HOMA-IR were higher, whereas the mean HDL-cholesterol levels and glutathione peroxidase (GPx) enzyme activity were significantly lower in obese subjects than controls. The linear regression analysis showed that lipid hydroperoxide was independently associated with only BMI, while ASP was independently associated with BMI and triglyceride. The present data support the concept that obesity occurs under condition of compex interactions by adipokines, insulin, inflammation, and oxidative stress.

Deficiency of C5L2 Increases Macrophage Infiltration and Alters Adipose Tissue Function in Mice

BackgroundObesity is considered as a systemic chronic low grade inflammation characterized by increased serum pro-inflammatory proteins and accumulation of macrophages within white adipose tissue (WAT) of obese patients. C5L2, a 7-transmembrane receptor, serves a dual function, binding the lipogenic hormone acylation stimulating protein (ASP), and C5a, involved in innate immunity.AimWe evaluated the impact of C5L2 on macrophage infiltration in WAT of wildtype (Ctl) and C5L2 knock-out (C5L2−/−) mice over 6, 12 and 24 weeks on a chow diet and moderate diet-induced obesity (DIO) conditions.ResultsIn Ctl mice, WAT C5L2 and C5a receptor mRNA increased (up to 10-fold) both over time and with DIO. By contrast, in C5L2−/−, there was no change in C5aR in WAT. C5L2−/− mice displayed higher macrophage content in WAT, varying by time, fat depot and diet, associated with altered systemic and WAT cytokine patterns compared to Ctl mice. However, in all cases, the M1 (pro-) vs M2 (anti-inflammatory) macrophage proportion was unchanged but C5L2−/− adipose tissue secretome appeared to be more chemoattractant. Moreover, C5L2−/− mice have increased food intake, increased WAT, and altered WAT lipid gene expression, which is reflected systemically. Furthermore, C5L2−/− mice have altered glucose/insulin metabolism, adiponectin and insulin signalling gene expression in WAT, which could contribute to development of insulin resistance.ConclusionDisruption of C5L2 increases macrophage presence in WAT, contributing to obesity-associated pathologies, and further supports a dual role of complement in WAT. Understanding this effect of the complement system pathway could contribute to targeting treatment of obesity and its comorbidities.

ASSA13-11-2 Relationship Between Novel Polymorphisms of the C5L2 Gene and Coronary Artery Disease

Objective C5L2, a G protein-coupled 7-transmembrane domain complement, has been demonstrated to be a functional receptor of acylation-stimulating protein (ASP), which is a stimulator of triglyceride synthesis or glucose transport. In this study, we will investingate the variations in the coding region of the C5L2 gene (C698T and G901A) and their association with coronary artery disease (CAD). Methods We identified novel single nucleotide polymorphisms (SNPs), (C698T and G901A) in exon 2 using a polymerase chain reaction direct-sequencing method. We examined the role of this SNP for CAD using two independent case-control studies: one was in the Han population (492 CAD patients and 577 control subjects) and the other was in the Uygur population (319 CAD patients and 554 control subjects). Results Using a polymerase chain reaction direct-sequencing method. We identified novel SNPs, 698C > T (P233L), and G901A (A300H) in exon 2. Heterozygote carriers of the 698CT genotype were more frequent among CAD patients than among controls not only in the Han population (7.3% versus 1.7%) but also in the Uygur population (4.7% versus 1.6%). The odds ratio ( OR ) for carriers of the 698CT genotype for CAD was 4.484 (95% confidence interval ( CI ): 2.197–9.174) in the Han group and 2.989 (95% CI : 1.292–6.909) in the Uygur population. After adjustment of confounding factors such as sex, age, smoking, alcohol consumption, hypertension, diabetes, as well as serum levels of triglyceride, total cholesterol, high-density lipoprotein, the difference remained significant in the Han group ( OR = 6.604, 95% CI : 2.776–15.711, P OR = 2.602, 95% CI : 1.015–6.671, P = 0.047). Heterozygote carriers of the 901GA genotype were more frequent among controls than among CAD patients not only in the Han population (8.6% versus 1.8%) but also in the Uygur population (5.2% versus 0.9%). The OR for carriers of the 901GA genotype for CAD in the Han population was 0.205 and 0.172 in the Uygur population. After adjustment of confounding factors, the difference remained significant in the Han group ( OR = 0.143, 95% CI : 0.068–0.302, P OR = 0.246, 95% CI : 0.072–0.837, P 2 = 22.713, P 2 = 19.022, P vs 0.008, P = 0.004); C-A haplotypefrequency in CAD group and the control group (0.026 vs 0.005, P = 0.001). Conclusions (1) C698T and the G901A in Han and Uygur population are association with coronary heart disease; (2) The 698CT and 901GA genotype of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China.

Complement‐mediated chronic inflammation is associated with diabetic microvascular complication

Chronic inflammation is characteristic of type 2 diabetes mellitus (T2DM). Obesity-activated adipocytes release adipocytokines, which induce the secretion of proinflammatory cytokines, resulting in vascular endothelial dysfunction and organ injury. C3a is a candidate to induce tissue inflammation. We investigated the association between diabetic microangiopathy and complement-mediated inflammation in 32 obese T2DM patients and 32 normal donors. Plasma levels of complement components and their activation intermediates were examined and related to the level of complication. An incubation study of post-prandial serum was carried out to measure the in vitro production of acylation stimulating protein (ASP/C3a desArg) by chylomicron. Plasma levels of C3, C4, factor B, iC3b, Bb, and ASP were significantly increased in T2DM patients. Levels of C4d and membrane attack complex (C5b-9) were not significantly elevated. The activation rate of these factors indicated that only the early phase of alternative complement pathway was excessively activated. A statistical study revealed close correlation between ASP, body mass index, and highly sensitive C-reactive protein. Plasma ASP was significantly increased in the macroalbuminuric and proliferative retinopathy patient groups. An incubation study revealed that ASP was produced after the in vitro incubation of post-prandial serum from a T2DM patient with hyperchylomicronaemia. Activation of the alternative complement pathway occurs in obese T2DM patients and is enhanced in the post-prandial hyperchylomicronic condition, which induces overproduction of ASP and C3a-mediated tissue inflammation. Therefore, complement-mediated inflammation may contribute to the acceleration of diabetic microangiopathy in addition to the development of macroangiopathy.

Relationship of C5L2 Receptor to Skeletal Muscle Substrate Utilization

ObjectiveTo investigate the role of Acylation Stimulating Protein (ASP) receptor C5L2 in skeletal muscle fatty acid accumulation and metabolism as well as insulin sensitivity in both mice and human models of diet-induced insulin resistance.Design and MethodsMale wildtype (WT) and C5L2 knockout (KO) mice were fed a low (LFD) or a high (HFD) fat diet for 10 weeks. Intramyocellular lipid (IMCL) accumulation (by oil red O staining) and beta-oxidation HADH enzyme activity were determined in skeletal muscle. Mitochondria were isolated from hindleg muscles for high-resolution respirometry. Muscle C5L2 protein content was also determined in obese type 2 diabetics and age- and BMI matched men.ResultsIMCL levels were increased by six-fold in C5L2KO-HFD compared to WT-HFD mice (p<0.05) and plasma insulin levels were markedly increased in C5L2KO-HFD mice (twofold, p<0.05). Muscle HADH activity was elevated in C5L2KO-LFD mice (+75%, p<0.001 vs. WT-LFD) and C5L2KO-HFD displayed increased mitochondrial fatty acid oxidative capacity compared to WT-HFD mice (+23%, p<0.05). In human subjects, C5L2 protein content was reduced (−48%, p<0.01) in type 2 diabetic patients when compared to obese controls. Further, exercise training increased C5L2 (+45%, p = 0.0019) and ASP (+80%, p<0.001) in obese insulin-resistant men.ConclusionThe results suggest that insulin sensitivity may be permissive for coupling of C5L2 levels to lipid storage and utilization.

Inflammatory Markers and Adipokines Alter Adipocyte-derived ASP Production Through Direct and Indirect Immune Interaction

Obesity and related metabolic diseases are associated with chronic low-grade inflammation, characterized by increased pro-inflammatory proteins. Several studies have demonstrated increases in acylation stimulating protein (ASP) and its precursor protein C3 in obesity, diabetes and dyslipidemia. To evaluate the effects of acute inflammatory factors and adipokines on ASP production and potential mechanisms of action, 3T3-L1 adipocytes were treated for 24 h with adipokines, cytokines, macrophage-conditioned media and direct co-culture with J774 macrophages. ASP and C3 in the media were evaluated in relation to changes in adipocyte lipid metabolism (cellular triglyceride stores). Leptin, adiponectin, IL-10, LPS and TNF-α increased ASP production (151%, 153%, 190%, 318%, 134%, P<0.05, respectively,). C5a and RANTES (Regulated and normal T cell expressed and secreted) decreased ASP production ( - 34%, - 47%, P<0.05), which was also associated with a decrease in the precursor protein C3 ( - 39% to - 51%, P<0.01), while keratinocyte chemoattractant (KC; murine IL-8 ortholog) had no effect on ASP and C3 secretion. By contrast, apelin, omentin and visfatin also decreased ASP ( - 27%, - 49%, - 22%, P<0.05), but without changes in precursor protein C3 secretion. Macrophage-conditioned media alone had little effect on C3 or ASP, while co-culture of adipocytes with macrophages markedly increased ASP and C3 production (272%, 167%, P<0.05). These in vitro results suggest various metabolic hormones and inflammatory factors can affect ASP production through increased precursor C3 production and/or by changing the rate of C3 conversion to ASP. As an adipokine, ASP could constitute a new link between adipocytes and macrophages.

Plasma Levels of Acylation-Stimulating Protein Are Strongly Predicted by Waist/Hip Ratio and Correlate with Decreased LDL Size in Men

The association of abdominal obesity with cardiovascular risk is often linked to altered secretion of adipose-derived factors and an abnormal lipid profile including formation of atherogenic small dense low density lipoprotein particles (sdLDL). Acylation-stimulating protein (ASP) is an adipose-derived hormone that exhibits potent lipogenic effects. Plasma ASP levels increase in obesity; however, the association of ASP levels with body fat distribution is not yet established, and no study to date has investigated the association of ASP with LDL size. In this study, we examined the association of ASP levels with abdominal obesity measures and the lipid profile including LDL size in 83 men with a wide range of abdominal girths. Regression analysis showed that waist/hip ratio was the main predictor of ASP levels (β = 0.52, P < 0.0001), significantly followed by decreased LDL size. BMI and TG levels, although positively correlated with ASP levels, were excluded as significant predictors in regression analysis. No correlation was found with LDL-C or apoB levels. ASP levels were 62.5% higher in abdominally obese compared to nonobese men. Waist/hip ratio presenting as the main predictor of ASP levels, suggests increased ASP production by abdominal fat which, as proposed previously, may result from resistance to ASP function causing delayed TG clearance and subsequent formation of atherogenic sdLDL.

Paradoxical Glucose-Sensitizing yet Proinflammatory Effects of Acute ASP Administration in Mice

Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system, which stimulates fat storage and is typically increased in obesity, type 2 diabetes, and cardiovascular disease. Using a diet-induced obesity (DIO) mouse model, the acute effects of ASP on energy metabolism and inflammatory processes in vivo were evaluated. We hypothesized that ASP would specifically exert proinflammatory effects. C57Bl/6 wild-type mice were put on a high-fat-high-sucrose diet for 12 weeks. Mice were then subjected to both glucose and insulin tolerance tests, each manipulation being preceded by recombinant ASP or vehicle (control) bolus injection. ASP supplementation increased whole-body glucose excursion, and this was accomplished with reduced concomitant insulin levels. However, ASP did not directly alter insulin sensitivity. ASP supplementation induced a proinflammatory phenotype, with higher levels of cytokines including IL-6 and TNF-α in plasma and in adipose tissue, liver, and skeletal muscle mRNA. Additionally, ASP increased M1 macrophage content of these tissues. ASP exerted a direct concentration-dependent role in the migration and M1 activation of cultured macrophages. Altogether, the in vivo and in vitro experiments demonstrate that ASP plays a role in both energy metabolism and inflammation, with paradoxical whole-body glucose-sensitizing yet proinflammatory effects.

Plasma Gamma-Glutamyltransferase Is Strongly Determined by Acylation Stimulating Protein Levels Independent of Insulin Resistance in Patients with Acute Coronary Syndrome

Background. Steatosis is a manifestation of the metabolic syndrome often associated with release of liver enzymes and inflammatory adipocytokines linked to cardiovascular risk. Gamma-glutamyltransferase (GGT) is one sensitive liver marker recently identified as an independent cardiovascular risk factor. Mechanisms involved in enhanced hepatic lipogenesis causing steatosis are not yet identified and are usually linked to insulin resistance (IR). Acylation stimulating protein (ASP), a potent lipogenic factor, was recently shown to increase in patients with steatosis and was implicated in its pathogenesis. Aim. To investigate the association of plasma ASP levels with liver and metabolic risk markers in acute coronary syndrome (ACS) patients. Methods. 28 patients and 30 healthy controls were recruited. Their anthropometrics, lipid profile, liver markers, insulin, and ASP levels were measured. Results. In the patients, ASP, liver, and metabolic risk markers were markedly higher than in the controls. ASP strongly predicted GGT levels (B = 0.75, P < 0.0001), followed by triglycerides (B = 0.403, P = 0.017), together determining 57.6% variation in GGT levels. Insulin and IR correlated with metabolic risk components but not with liver enzymes. Conclusion. The strong association of ASP with GGT in ACS patients suggests that ASP, independent of IR, may contribute to a vicious cycle of hepatic lipogenic stimulation and GGT release promoting atherogenesis.

State of the art paper Biochemistry of adipose tissue: an endocrine organ

Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre-adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). This paper reviews some of the biochemical and metabolic aspects of adipose tissue and its relationship to inflammatory disease and insulin resistance.

C5L2 and C5aR interaction in adipocytes and macrophages: Insights into adipoimmunology

Obesity is associated with inflammation characterized by increased infiltration of macrophages into adipose tissue. C5aR-like receptor 2 (C5L2) has been identified as a receptor for acylation-stimulating protein (ASP) and the inflammatory factor C5a, which also binds C5aR. The present study examines the effects of ligands ASP and C5a on interactions between the receptors C5L2 and C5aR in 3T3-L1 adipocytes and J774 macrophages.BRET experiments indicate that C5L2 and C5aR form homo- and heterodimers in transfected HEK 293 cells, which were stable in the presence of ligand. Cell surface receptor levels of C5L2 and C5aR increased during 3T3-L1 adipocyte differentiation; both receptors are also highly expressed in J774 macrophages. Using confocal microscopy to evaluate endogenous receptors in adipocytes following stimulation with ASP or C5a, C5L2 is internalized with increasing perinuclear colocalization with C5aR. There is little C5a-dependent colocalization in macrophages. While adipocyte-conditioned medium (ACM) increased C5L2–C5aR colocalization in macrophages, this was blocked by C5a. ASP stimulation increased Akt (Ser473) phosphorylation in both cell types; C5a induced slight Akt phosphorylation in adipocytes with less effect in macrophages. ASP, but not C5a, increased fatty acid uptake/esterification in adipocytes.C5L2–C5aR homodimerization versus heterodimerization may thus contribute to differential responses obtained following ASP vs C5a stimulation of adipocytes and macrophages, providing new insights into the complex interaction between these two cell types within adipose tissue. Studying the mechanisms involved in the differential responses of C5L2–C5aR activation based on cell type will further our understanding of inflammatory processes in obesity.

Differential chemoattractant response in adipocytes and macrophages to the action of acylation stimulating protein

Obesity is characterized by chronic low-grade inflammation with increased adipose tissue pro-inflammatory cytokine production. Acylation stimulating protein (ASP) stimulates triglyceride synthesis and glucose transport via its receptor C5L2. Circulating ASP is increased in obesity, insulin resistance and metabolic syndrome. The present study examines the effects of normal (50nM), high physiological (200nM) and pathological (600nM) levels of ASP on inflammatory changes in 3T3-L1 adipocytes and J774 macrophages and the underlying mechanisms involved. Treatment with ASP for 24h increased monocyte chemoattractant protein-1 (MCP1, 800%, P<0.001) and keratinocyte-derived chemokine (KC, >150%, P<0.01) secretion in adipocytes in a dose-dependent manner, with no effect on IL-6 or adiponectin. In macrophages, ASP had no effect on these cytokines. C5a, a ligand for C5L2 and C5aR receptors, differed from ASP. Macrophage-adipocyte coculture increased MCP-1 and adiponectin secretion, and ASP further enhanced secretion (P<0.001 and P<0.05, respectively) at doses of 50nM and 200nM. ASP increased Ser468 and Ser536 phosphorylation of p65 NFκB in a time- and concentration-dependent manner (P<0.05) as well as phosphorylation of Akt Ser473 (p=0.02). ASP and insulin stimulations of Ser536 p65 NFκB phosphorylation were comparable (both p<0.05) but not additive. Both inhibition of PI3kinase (with wortmannin) and NFκB (with BAY11-7085) prevented ASP stimulation of MCP-1 and KC secretion in adipocytes. These findings suggest that ASP, especially at high physiologic doses, may stimulate specific inflammatory cytokines in adipocytes through PI3kinase- and NFκB-dependant pathways, thus further promoting macrophage infiltration and local inflammation in obese adipose tissue.

Recombinant Acylation Stimulating Protein Administration to C3−/− Mice Increases Insulin Resistance via Adipocyte Inflammatory Mechanisms

BackgroundComplement 3 (C3), a key component of the innate immune system, is involved in early inflammatory responses. Acylation stimulating protein (ASP; aka C3adesArg), a C3 cleavage product, is produced in adipose tissue and stimulates lipid storage. We hypothesized that, depending on the diet, chronic ASP administration in C3−/− mice would affect lipid metabolism and insulin sensitivity via an adaptive adipose tissue inflammatory response.Methodology/Principal FindingsC3−/− mice on normal low fat diet (ND) or high fat diet (HFD) were chronically administered recombinant ASP (rASP) for 25 days via an osmotic mini-pump. While there was no effect on food intake, there was a decrease in activity, with a relative increase in adipose tissue weight on ND, and a shift in adipocyte size distribution. While rASP administration to C3−/− mice on a ND increased insulin sensitivity, on a HFD, rASP administration had the opposite effect. Specifically, rASP administration in C3−/− HFD mice resulted in decreased gene expression of IRS1, GLUT4, SREBF1 and NFκB in muscle, and decreased C5L2 but increased JNK, CD36, CD11c, CCR2 and NFκB gene expression in adipose tissue as well as increased secretion of proinflammatory cytokines (Rantes, KC, MCP-1, IL-6 and G-CSF). In adipose tissue, although IRS1 and GLUT4 mRNA were unchanged, insulin response was reduced.ConclusionThe effects of chronic rASP administration are tissue and diet specific, rASP administration enhances the HFD induced inflammatory response leading to an insulin-resistant state. These results suggest that, in humans, the increased plasma ASP associated with obesity and cardiovascular disease could be an additional factor directly contributing to development of metabolic syndrome, insulin resistance and diabetes.

RELATIONSHIP BETWEEN NOVEL POLYMORPHISMS OF THE C5L2 GENE AND CORONARY ARTERY DISEASE

ObjectivesC5L2, a G protein-coupled 7-transmembrane domain complement, has been demonstrated to be a functional receptor of acylation-stimulating protein (ASP), which is a stimulator of triglyceride synthesis or glucose transport. In...

Acylation stimulating protein reduction precedes insulin sensitization after BPD-DS bariatric surgery in severely obese women

Objective:The mechanisms involved in early resolution of insulin resistance and type 2 diabetes mellitus after biliopancreatic diversion with duodenal switch (BPD-DS) surgery are still unknown. We evaluated early effects of BPD-DS on plasma acylation stimulating protein (ASP), an adipokine involved in lipid and glucose metabolism.Subjects:32 non-diabetic and 22 diabetic severely obese women (BMI⩾40 kg m−2) were evaluated for body composition and plasma parameters before, 24 h, 5 days, 6 and 12 months after surgery.Results:Within the early postoperative period (24 h), ASP decreased 25 and 30% in non-diabetic and diabetic women, respectively (P<0.001). Twenty-four hours after surgery, triglyceride, cholesterol, HDL-Chol, LDL-Chol and C3 also decreased, while glucose, insulin and high-sensitivity C-reactive protein (hsCRP) increased (all P<0.001). By 5 days, without significant weight loss, the decreases in ASP, cholesterol, HDL-Chol and LDL-Chol levels were all maintained. At this time, glucose, insulin and HOMA-IR also decreased 11 to 52% (all P<0.001). At 6 and 12 months, with pronounced weight loss and decreased per cent fat mass, there were further decreases in ASP (maximal −56% non-diabetic, −61% diabetic, P<0.001), as well as in glucose, insulin, HOMA-IR, triglyceride, cholesterol, LDL-Chol, HDL-Chol and hsCRP levels. Improved insulin resistance/diabetes at 5 days was predicted by 24 h changes as follows: per cent change ASP, HDL-Chol, hsCRP and total cholesterol predicted HOMA-IR (5 days) (r2=0.454, P<0.001), and per cent change ASP, HDL-Chol and hsCRP predicted change (5 days vs baseline) in HOMA-IR (r2=0.351, P<0.001).Conclusion:Acute postoperative decreases in ASP are associated with early improvement of insulin resistance/diabetes after BPD-DS surgery.

Relationship between a novel polymorphism of C5L2 gene C698T and type 2 diabetes in Uygur population of Xinjiang region

Objective To investigate the relationship between a novel polymorphism of C5L2 gene and type 2 diabetes mellitus (T2DM) in Uygur population from Xinjiang region.Methods A novel single nucleotide polymorphism(SNP),698C＞T(P233L) was found using a polymerase chain reaction direct-sequencing method.C5L2 gene 698C ＞ T variant from 252 patients with T2DM and 747 healthy control subjects was detected by polymerase chain reaction and restriction fragment length polymorphism.Result Heterozygote carriers of the 698CT genotype were more frequent among T2DM patients than that among controls (0.107 vs 0.036,x2 =18.576,P＜0.01) in the Uygur population. After adjustment of confounding factors such as sex,age,smoking,alcohol consumption,and hypertension,as well as serum levels of triglyceride,total cholesterol,low-density lipoproteincholesterol,and high-density lipoprotein-cholesterol,the difference remained significant ( P＜0.01,OR =3.373,95％ CI 1.736-6.553 ).Conclusion The CT genotype of the C5L2 gene might be a risk factor of T2DM in Uygur nationality population in Xinjiang. Key words: C5L2 gene; Acylation-stimulating protein; Diabetes mellitus, type 2; Uygur

Apparent Sex-Specific Divergence of Acylation Stimulating Protein Levels With Respect to Metabolic Parameters of Pathogenetic and Clinical Relevance

Background: Acylation stimulating protein (ASP) is an adipose tissue-derived hormone that regulates triglyceride (TG) synthesis and glucose transport. Associations of ASP and / or its precursor complement C3 have been demonstrated with obesity, insulin resistance, diabetes, and cardiovascular diseases. We determined fasting serum ASP in a Turkish adult population sample and assessed relationships with cardiometabolic risk factors. Methods: Cross-sectional population-based study recruiting 224 men and women from the Turkish Adult Risk Factor (TARF) study. Results: Geometric Mean ASP levels (median) in women (271 nmol / L) tended to be lower than men (305 nmol / L) (P = 0.059), and this was also true in most subgroups with vs . without cardiometabolic disorders. Interestingly, correlations of ASP diverged in direction across genders with TG, glucose, height, age and other risk variables. Conclusion: Gender divergence is an aspect of this Turkish population that has been noted for various lipid parameters (HDL, Lp(a)), association of cardiometabolic risk with smoking and alcohol intake and the response of the pro-inflammatory state to adiposity. This is consistent in the present study, where metabolic states correlate with ASP, but are divergent between genders. doi:10.4021/jem58w

Apparent Sex-Specific Divergence of Acylation Stimulating Protein Levels With Respect to Metabolic Parameters of Pathogenetic and Clinical Relevance

Background: Acylation stimulating protein (ASP) is an adipose tissue-derived hormone that regulates triglyceride (TG) synthesis and glucose transport. Associations of ASP and / or its precursor complement C3 have been demonstrated with obesity, insulin resistance, diabetes, and cardiovascular diseases. We determined fasting serum ASP in a Turkish adult population sample and assessed relationships with cardiometabolic risk factors. Methods: Cross-sectional population-based study recruiting 224 men and women from the Turkish Adult Risk Factor (TARF) study. Results: Geometric Mean ASP levels (median) in women (271 nmol / L) tended to be lower than men (305 nmol / L) (P = 0.059), and this was also true in most subgroups with vs . without cardiometabolic disorders. Interestingly, correlations of ASP diverged in direction across genders with TG, glucose, height, age and other risk variables. Conclusion: Gender divergence is an aspect of this Turkish population that has been noted for various lipid parameters (HDL, Lp(a)), association of cardiometabolic risk with smoking and alcohol intake and the response of the pro-inflammatory state to adiposity. This is consistent in the present study, where metabolic states correlate with ASP, but are divergent between genders. J Endocrinol Metab. 2012;2(1):1-10 doi: https://doi.org/10.4021/jem58w

Relationship between type 2 diabetes mellitus and a novel polymorphism C698T in C5L2 in the Chinese Han population

In a previous study, we reported a novel single nucleotide polymorphism (SNP) 698C>T (P233L) in the gene, C5L2. This gene has been demonstrated to encode a functional receptor of acylation-stimulating protein (ASP), a G-protein-coupled receptor (GPCR), that has been shown to influence insulin secretion in cultured pancreatic islet cells in vitro and is a stimulator of triglyceride synthesis and glucose transport in vivo. In this study, we evaluated the relationship between this novel C5L2 SNP and development of type 2 diabetes mellitus (T2DM) in the Chinese Han population. A case-control study examining Chinese Han T2DM patients (n=554) and healthy controls (n=648) was performed to investigate the role of the 698C>T (P233L) C5L2 polymorphism. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to determine expression of this SNP. Heterozygote carriers of the 698CT C5L2 genotype were more frequent among T2DM patients (13.5%) than controls (3.2%; P<0.001). The frequency of 698CT heterozygote carriers was significantly higher in women (12.8%) than in male subjects (5.7%, P<0.001). The odds ratio (OR) of T2DM for 698CT carriers was 4.675 [95% confidence interval (CI) 2.840-7.694]. After adjustment of confounding factors such as age, sex, smoking, drinking, hypertension, and triglyceride (TG), total cholesterol, high-density lipoprotein, and low-density lipoprotein levels, the difference remained significant (P<0.001, OR 5.556, 95% CI 2.444-12.630). Furthermore, the diabetic 698CT carriers displayed an increase in their serum TG level. However, there were no significant differences observed in any of the parameters measured in the control group. We conclude that the 698CT genotype of C5L2 may be an influencing genetic factor for T2DM in the Chinese Han population. These findings also indicate that heterozygous expression of 698CT C5L2 may contribute to metabolic abnormalities.