Acylation Stimulating Protein Research Articles

Association of complement components with the risk and severity of NAFLD: A systematic review and meta-analysis.

It is generally believed that complement system is strongly associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, complement system contains a variety of complement components, and the relationship between complement components and the risk and severity of NAFLD is inconsistent. The aim of this meta-analysis was to evaluate the association of complement components with the risk and severity of NAFLD. We searched PubMed, Embase, Cochrane Library, Google Scholar, Scopus, and ZhiWang Chinese databases from inception to May 2022 for observational studies reporting the risk of NAFLD with complement components. Random-effects meta-analysis was used to obtain pooled estimates of the effect due to heterogeneity. We identified 18 studies with a total of 18560 included subjects. According to recent studies, levels of complement component 3 (C3) (mean difference (MD): 0.43, 95% confidence interval (CI) 0.26-0.60), complement component 4 (C4) (MD: 0.04, 95% CI 0.02-0.07), complement component 5(C5) (MD: 34.03, 95% CI 30.80-37.27), complement factor B (CFB) (MD: 0.22, 95% CI 0.13-0.31) and acylation stimulating protein (ASP) (standard mean difference (SMD): 5.17, 95% CI 2.57-7.77) in patients with NAFLD were significantly higher than those in the control group. However, no statistical significance was obtained in complement factor D (CFD) levels between NAFLD and non-NAFLD (MD=156.51, 95% CI -59.38-372.40). Moreover, the levels of C3, C5, CFB, and ASP in patients with moderate and severe NAFLD were significantly higher than those in patients with mild NAFLD. Except for C4 and CFD, the included studies did not explore the changes in the severity of NAFLD according to the concentration of C4 and CFD. This meta-analysis demonstrates that an increase in complement components including C3, C5, CFB, and ASP is associated with an increased risk and severity of NAFLD, indicating that they may be good biomarkers and targets for the diagnosis and treatment of NAFLD. PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42022348650.

Acylation-stimulating protein and heart failure progression in arrhythmogenic right ventricular cardiomyopathy.

Our previous studies suggested that the complement system was critical in the prognosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). The acylation-stimulating protein (ASP), generated through the alternate complement pathway, was reported to regulate lipogenesis and triglyceride storage. This study aimed to investigate the role of ASP in predicting adverse cardiac events in an ARVC cohort. We enrolled 111 ARVC patients and 106 healthy volunteers, and measured their plasma ASP levels using enzyme-linked immunosorbent assays. Plasma ASP levels were significantly higher in the ARVC patients than in the healthy controls (2325.22±20.08 vs. 2189.75±15.55, P<0.001), with a similar trend observed in the myocardial explant assay. Spearman correlation analysis indicated plasma ASP level associated with cardiac structural (right ventricular internal dimension, P=0.006) and functional remodelling (left ventricular ejection fraction, P=0.002) in ARVC patients. The ARVC patients were followed up for an average of 17.79±1.09months. Heart failure-associated events (HFAEs) were defined as heart transplantation, on a cardiac transplant list, or death due to end-stage heart failure. Plasma ASP levels in patients with HFAEs were significantly higher than in those without clinical events (2486.03±26.70 vs. 2268.83±23.51, P<0.001) or those with malignant arrhythmic events (2486.03±26.70 vs. 2297.80±60.46, P=0.008). LASSO (least absolute shrinkage and selection operator) and multivariable Cox regression analyses showed the ASP level (HR=1.004, 95% CI [1.002,1.006], P=0.002) was an independent predictor for adverse HFAEs in ARVC patients. The spline-fitting procedure was applied to illustrate the HFAE-free probabilities at different time points. Our results suggest that plasma ASP may be a useful biomarker in prediction of adverse HF-associated events in ARVC patients.

The role of complement in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver diseases globally. NAFLD includes a range of hepatic manifestations, starting with liver steatosis and potentially evolving towards nonalcoholic steatohepatitis, cirrhosis or even hepatocellular carcinoma. Although the pathogenesis of NAFLD is incompletely understood, insulin resistance and lipid metabolism disorder are implicated. The complement system is an essential part of the immune system, but it is also involved in lipid metabolism. In particular, activation of the alternative complement pathway and the production of complement activation products such as C3a, C3adesArg (acylation stimulating protein or ASP) and C5a, are strongly associated with insulin resistance, lipid metabolism disorder, and hepatic inflammation. In this review, we briefly summarize research on the role of the complement system in NAFLD, aiming to provide a basis for the development of novel therapeutic strategies for NAFLD.

Roux-en-Y Gastric Bypass Surgery Has Early Differential Effects on Bile Acids and the Levels of Complement Component 3 and Acylation-Stimulating Protein.

Bile acids have been implicated in the mechanism by which Roux-en-Y gastric bypass (RYGB) can induce remission of type 2 diabetes (T2D). Our goal was to identify circulating proteins whose levels changed after RYGB when dysglycemic parameters normalized. This was a retrospective study of 26 participants who underwent RYGB. Blood proteins were identified using two-dimensional electrophoresis and mass spectroscopy. Complement proteins were measured using immunoassays and bile acids measured using ultra-high-performance liquid chromatography and mass spectroscopy. A total of 7/452 blood proteins were found to change 2days after RYGB. Complement component 3 (C3) was selected because of its regulation by bile acids and the glucoregulatory function of its proteolytically processed product C3adesArg or acylation-stimulating protein (ASP). The median (inter-quartile range/IQR) C3 level was 47.4 (34.5, 65.9) mg/dL before surgery decreasing to 40.9 (13.4, 64.1) mg/dL within 2days after surgery (p = 0.0292). The median (IQR) ASP level increased from 2.8 (0.9, 7.3) nM before surgery to 8.0 (5.3, 14.1) nM within 2days after surgery (p = 0.0016). ASP levels increased in 14/17 (82%) with T2D remission and in 6/6 with normoglycemia but decreased in 3/3 with persistent T2D. Of ten bile acids measured, the levels of ursodeoxycholic acid (UDCA) were significantly decreased after RYGB and the levels of taurodeoxycholic acid (TDCA) were significantly decreased with T2D remission. These data further support an association of C3 with glucose metabolism and implicate bile acids and ASP in the early remittive effects of RYGB on T2D.

Role of Complement and Complement-Related Adipokines in Regulation of Energy Metabolism and Fat Storage.

Adipose tissue releases many cytokines and inflammatory factors described as adipokines. In obesity, adipokines released from expanding adipose tissue are implicated in disease progression and metabolic dysfunction. However, mechanisms controlling the progression of adiposity and metabolic complications are not fully understood. It has been suggested that expanding fat mass and sustained release of inflammatory adipokines in adipose tissue lead to hypoxia, oxidative stress, apoptosis, and cellular damage. These changes trigger an immune response involving infiltration of adipose tissue with immune cells, complement activation and generation of factors involved in opsonization and clearance of damaged cells. Abundant evidence now indicates that adipose tissue is an active secretory source of complement and complement-related adipokines that, in addition to their inflammatory role, contribute to the regulation of metabolic function. This article highlights advances in knowledge regarding the role of these adipokines in energy regulation of adipose tissue through modulating lipogenic and lipolytic pathways. Several adipokines will be discussed including adipsin, Factor H, properdin, C3a, Acylation-Stimulating Protein, C1q/TNF-related proteins, and response gene to complement-32 (RGC-32). Interactions between these factors will be described considering their immune-metabolic roles in the adipose tissue microenvironment and their potential contribution to progression of adiposity and metabolic dysfunction. The differential expression and the role of complement factors in gender-related fat partitioning will also be addressed. Identifying lipogenic adipokines and their specific autocrine/paracrine roles may provide means for adipose-tissue-targeted therapeutic interventions that may disrupt the vicious circle of adiposity and disease progression. © 2019 American Physiological Society. Compr Physiol 9:1411-1429, 2019.

The Effect of Atorvastatin (and Subsequent Metformin) on Adipose Tissue Acylation-Stimulatory-Protein Concentration and Inflammatory Biomarkers in Overweight/Obese Women With Polycystic Ovary Syndrome.

Background: Atorvastatin has been shown to improve cardiovascular risk (CVR) indices in women with polycystic ovary syndrome (PCOS). Low-grade chronic inflammation of adipose tissue may link PCOS and adverse CVR. In pro-inflammatory states such as PCOS, spontaneous activation of the alternative pathway of complement results in increased generation of acylation stimulating protein (ASP) from adipocytes irrespective of body mass index.Methods: The objective of this study was to determine the effect of atorvastatin on markers of adipose tissue dysfunction and inflammation; acylation-stimulating-protein (ASP), interleukin-6 (IL-6), and monocyte-chemoattractant-protein-1 (MCP-1) in PCOS. This was a randomized, double-blind, placebo-controlled study where 40 medication-naive women with PCOS and biochemical hyperandrogenaemia were randomized to either atorvastatin 20 mg daily or placebo for 12 weeks. Following the 12 week randomization; both group of women with PCOS were subsequently started on metformin 1,500 mg daily for further 12 weeks to assess whether pre-treatment with atorvastatin potentiates the effects of metformin on markers of adipose tissue function We conducted a post-hoc review to detect plasma ASP and the pro-inflammatory cytokines IL6 and MCP-1 before and after 12 and 24 weeks of treatment.Results: There was significant reduction in ASP (156.7 ± 16.2 vs. 124.4 ± 14.8 ng/ml p <0.01), IL-6 (1.48 ± 0.29 vs.0.73 ± 0.34 pg/ml p = 0.01) and MCP-1 (30.4 ± 4.2 vs. 23.0 ± 4.5 pg/ml p = 0.02) after 12 weeks of atorvastatin that was maintained subsequently with 12 weeks treatment with metformin. There was a significant positive correlation between ASP levels with CRP (p < 0.01), testosterone (p < 0.01) and HOMA-IR (p < 0.01); IL-6 levels with CRP (p <0.01) and testosterone (p < 0.01) and MCP-1 with CRP (p < 0.01); testosterone (p < 0.01) and HOMA-IR (p < 0.02).Conclusions: This post-hoc analysis revealed that 12 weeks of atorvastatin treatment significantly decreased the markers of adipose tissue dysfunction and inflammation, namely ASP, IL-6 and MCP-1 in obese women with PCOS. Changes in adipose tissue markers were significantly associative with substantial improvements in HOMA-IR, testosterone and hs-CRP levels.ISRCTN Number: ISRCTN24474824.

Role of Adipokines in Development of Metabolic Syndrome

Visceral adipose tissue releases a variety of adipokines which together determine a comprehensive cardiometabolic risk profile. Estrogen deficiency leads to central fat deposition in postmenopausal women. However, premenopausal women are also running high risk of central obesity owing to unhealthy lifestyles, making them prone to development of metabolic syndrome which leads to infertility, polycystic ovary syndrome (PCOS), insulin resistance, and type 2 diabetes (T2D). Premenopausal women with (n=30) and without (n=30) central obesity were studied. Metabolic risk factors and circulatory adipokines were measured. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Adipokines' gene polymorphisms were studied by polymerase chain reaction and mRNA expression of leptin, adiponectin, resistin, and interleukin-6 (IL-6). Tumour necrosis factor-α (TNF-α), acylation stimulating protein (ASP) receptor gene (C5L2) were done by real time-polymerase chain reaction in visceral (VAT) and subcutaneous (SAT) adipose tissues was also obtained. Significant high circulating leptin, IL-6, TNF-α, resistin and their VAT mRNA expression and significant low circulating adiponectin and VAT mRNA expression were found in women with metabolic syndrome, irrespective of their menopausal status. Carriers of mutant genotype of TNF-α 308 AA, IL-6 174 CC, resistin 420 GG, leptin 2549 AA, adiponectin 276 TT and C5L2 698 CT had significant association with metabolic syndrome. Conclusively changes in fat distribution modulate the secretion profile of adipokines, therefore elevated circulating leptin, IL-6, TNF-α, ASP, resistin, and low adiponectin may serve as surrogate markers for metabolic syndrome and related morbidities in women with central obesity.

Association of A:O ratio with metabolic risk markers in North Indian women

BackgroundPlasma concentrations of Acylation stimulating protein (ASP) and Orexin-A are closely linked to body weight and energy homeostasis. The purpose of this study is to describe the associations of A:O with metabolic risk marker in women. MethodsThis is a case control study. Total 382 women were recruited for the study.192 women with metabolic syndrome (WmetS) &190 women without metabolic syndrome (WometS) according to NCEP-ATPIII guidelines. Serum ASP and Orexin-A level were determined by enzyme linked immunosorbent assay. ResultsResult indicated that Waist Circumference, Blood pressure, Lipid profile, Glucose (FPG), Insulin resistance (HOMA-IR), ASP and A:O ratio were significantly higher but HDL and Orexin-A level were significantly lower in WmetS than WometS. The correlation of ASP, A:O ratio were positively significant correlated with Waist Circumference (WC), Triglyceride (TG), Glucose (FPG) and negatively significant correlated with High density lipoprotein (HDL), however the orexin-A was negatively significant correlated with WC and TG in WmetS. ConclusionThe study concluded that A:O ratio may be one of the potential biomarker for metabolic syndrome.

Complement Factor C3 Methylation and mRNA Expression Is Associated to BMI and Insulin Resistance in Obesity.

Epigenetic marks, and especially DNA methylation, are becoming an important factor in obesity, which could help to explain its etiology and associated comorbidities. Adipose tissue, now considered as an important endocrine organ, produces complement system factors. Complement component 3 (C3) turns out to be an important protein in metabolic disorders, via either inflammation or the C3 subproduct acylation stimulating protein (ASP) which directly stimulates lipid storage. In this study, we analyze C3 DNA methylation in adipose tissue from subjects with a different grade of obesity. Adipose tissue samples were collected from subjects with a different degree of obesity determined by their body mass index (BMI) as: Overweight subjects (BMI ≥ 25 and <30), obese class 1/2 subjects (BMI ≥ 30 and <40) and obese class 3 subjects (BMI ≥ 40). C3 DNA methylation was measured for 7 CpGs by pyrosequencition using the Pyromark technology (Qiagen, Madrid Spain). C3 messenger RNA (mRNA) levels were analyzed by pre-designed Taqman assays (Applied biosystems, Foster City, CA, USA) and ASP/C3a was measured using a ELISA kit. The data were analyzed using the statistic package SPSS. C3 DNA methylation levels were lower in the morbid obese group. Accordingly, C3 methylation correlated negatively with BMI and leptin. However, C3 mRNA levels were more associated with insulin resistance, and positive correlations with insulin, glucose and homeostasis model assessment-estimated insulin resistance (HOMA-IR) existed. ASP correlated negatively with high density lipoprotein (HDL) cholesterol. C3 methylation levels were associated to adiposity variables, such as BMI and leptin, while the C3 mRNA levels were associated to glucose metabolism.

Association of acylation stimulating protein and adiponectin with metabolic risk marker in North Indian obese women

BackgroundPlasma concentrations of Acylation stimulating protein (ASP) and adiponectin are associated with body weight and energy homeostasis. The purpose of this study is to describe the potential role of acylation stimulating protein and adiponectin with metabolic risk marker in North Indian obese women. MethodsThis is a case control study. Total 520 women were recruited for the study n = 260 women with obesity (BMI>30) study group and n = 260 women without obesity (BMI<25) control group. Serum ASP and adiponectin level were determined by enzyme linked immunosorbent assay. ResultsResult indicated that WC, BP, lipid profile, FPG, FPI, IR (HOMA-IR), ASP were significantly higher but adiponectin and HDL were significantly lower in women with obesity than in women without obesity. Furthermore ASP was significantly positive correlated with WC, FPG, TG, VLDL, FPI and IR, whereas the correlation of adiponectin was significantly negative correlated with WC, FPG, TG, IR, ASP and significantly positive correlated with HDL in women with obesity. ConclusionThe study shows that high level of ASP and low level of Adiponectin could be a potential marker of women with obesity among metabolic syndrome.

The Emerging Role of Complement C3 as A Biomarker of Insulin Resistance and Cardiometabolic Diseases: Preclinical and Clinical Evidence.

An intricate network of reciprocal interactions between adipose tissue and immune system have been largely demonstrated, leading to the well-accepted concept of insulin resistance as a low grade inflammatory state and, conversely, chronic high-grade inflammation as a dysmetabolic condition. Immune homeostasis is regulated by several players including the complement system, a complex protein network at the crossroad between the innate and adaptive arms of the human defences against pathogens. Complement C3 represents the nodal point of the complement cascade independently of the pathway recruited. Aim of this review is to collect the evidence supporting the role of complement C3 as a candidate biomarker of insulin resistance and other metabolic disorders. We reviewed the available evidence pointing to a role of complement system, and in particular complement C3, in insulin resistance and other cardiometabolic diseases including diabetes (T2D), hypertension, non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. Compelling preclinical evidence demonstrated a role of adipose-tissue C3 and its cleavage products C3a and acylation stimulating protein (ASP) in adipose tissue inflammation and insulin resistance. To further support this hypothesis, several clinical studies, both cross-sectional and longitudinal, confirmed this association in independent cohorts. Moreover, preliminary evidence support a role of complement C3 in other cardiometabolic diseases such as hypertension, NAFLD and atherosclerosis. Future studies are needed to fully confirm the usefulness of C3 as a clinical biomarker and to establish accurate cut-off values. Moreover, the therapeutic potential of C3 modulation in either cardiometabolic and inflammatory diseases need to be investigated.

Acylation-stimulating protein is a surrogate biomarker for acute myocardial infarction: Role of statins.

BACKGROUND:Acylation-stimulating protein (ASP) is an adipokine synthesized within adipocytes environment due to adipocyte differentiation.AIM:The aim of this study was to assess changes in ASP levels in patients with acute myocardial infarction (MI) and to correlate these variations with disease variables.SUBJECTS AND METHODS:A total number of 111 patients previously and currently treated with rosuvastatin or atorvastatin presented with acute MI in a Coronary Care Unit, were divided into three groups, Group A: Thirty-nine patients treated with atorvastatin, Group B: Thirty patients treated with rosuvastatin, compared to 42 patients presented with MI not previously treated with statins were enrolled in this study. ASP and troponin-I levels and lipid profile were estimated in each group.RESULTS:The effects of atorvastatin and rosuvastatin compared to nonstatins-treated group on the anthropometric and biochemical variables in patients with acute MI showed significant difference in all biochemical and anthropometric parameters P < 0.05. Serum ASP (nmol/l) levels were higher in control patients 57.25 ± 9.15 compared to atorvastatin-treated patients 48.43 ± 7.42 and rosuvastatin-treated patients 49.33 ± 6.52 P = 0.0124.CONCLUSION:ASP levels are elevated in patients with acute MI and regarded as surrogate biomarker for acute MI also; therapy with statins leads to significant reduction in ASP levels compared to nonstatins-treated patients that presented with acute MI.

An increase level of acylation stimulating protein is correlated with metabolic risk markers in North Indian obese women

Background and aimsThe present study was to investigate the association between serum acylation stimulating protein (ASP) level with metabolic risk factors in North Indian obese women. MethodsThis is a case control study, total n=322 women aged between 20 and 45 years (n=162 with metabolic syndrome & n=160 without metabolic syndrome) were recruited for the study according to National Cholesterol Education Program Treatment Panel (NCEPATP) guidelines. Serum ASP level were determined by enzyme linked immunosorbent assay. ResultsResults indicated that circulating ASP and other metabolic risk factors (waist circumference, triglycerides, fasting plasma glucose etc) were significantly higher in women with metabolic syndrome (WmetS) than in women without syndrome (WometS) (p<0.001). Furthermore circulating ASP was significantly higher possitively correlated with waist circumference (r=0.51, p<0.001), triglyceride (r=0.56, p<0.001), glucose (r=0.70, p<0.001), and negatively correlated with high density lipoprotein(r=−0.56, p<0.001) in women with metabolic syndrome. ConclusionsConclusively circulating ASP was found to be significantly associated with hyperlipidemia, obesity and obesity related disorders in North Indian obese women.

Cholinergic activation suppresses palmitate-induced macrophage activation and improves acylation stimulating protein resistance in co-cultured adipocytes.

Acylation-stimulating protein (ASP), produced through activation of the alternative complement immune system, modulates lipid metabolism. Using a trans-well co-culture cell model, the mitigating role of α7-nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic pathway on ASP resistance was evaluated. ASP signaling in adipocytes via its receptor C5L2 and signaling intermediates Gαq, Gβ, phosphorylated protein kinase C-α, and protein kinase C-ζ were markedly suppressed in the presence of TNFα or medium from palmitate-treated RAW264.7 macrophages, indicating ASP resistance. There was no direct effect of α7nAChR activation in 3T3-L1 cell culture. However, α7nAChR activation almost completely reversed the ASP resistance in adipocytes co-cultured with palmitate-treated RAW264.7 macrophages. Further, α7nAChR activation could suppress the production of pro-inflammatory molecules TNFα and interleukin-6 produced from palmitate-treated co-cultured macrophages. These results suggest that macrophages play a significant role in the pathogenesis of ASP resistance and α7nAChR activation secondarily improves adipose ASP resistance through suppression of inflammation in macrophages. Impact statement 1. Adipocyte-macrophage interaction in acylation-stimulating protein (ASP) resistance 2. Lipotoxicity induced inflammatory response in ASP resistance 3. A vicious circle between lipotoxicity and inflammatory response in ASP resistance 4. Cholinergic modulation of inflammatory response in adipocyte and macrophage.

Components of the alternative complement pathway in patients with psoriasis.

Psoriasis is a chronic inflammatory skin disease. Adipose tissue plays important roles in the events that regulate body metabolism. This study determined the levels of complement 3 ( C3), acylation-stimulating protein (ASP), and adipsin, which take part in the alternate complement pathway, and are synthesized in and secreted by adipose tissue. Thirty-two patients with psoriasis were matched with 22 controls in terms of age, sex, body mass index, and lipid profiles. Serum C3, ASP, and adipsin levels were measured in both groups. The serum C3 level was higher and ASP and adipsin levels were lower in the patient group, but these differences were not significant (p = 0.708, p = 0.628, and p = 0.218, respectively). ASP and adipsin levels were correlated positively in patients with psoriasis (p = 0.029). To our knowledge, this study is the first to evaluate ASP and adipsin levels in patients with psoriasis. The roles of ASP and adipsin in the etiopathogenesis of psoriasis are unclear. Although not statistically significant, the lower ASP and adipsin levels in the patient group suggest a potential anti-inflammatory role of these proteins in psoriasis. Further studies should examine the relationships between ASP/adipsin and psoriasis.

Association of C5L2 genetic polymorphisms with coronary artery disease in a Han population in Xinjiang, China.

BackgroundC5aR-like receptor 2 (C5L2) has been identified as a receptor for the inflammatory factor Complement 5a (C5a) and acylation-stimulating protein (ASP). ASP binding to C5L2 leading to a net accumulation of TG stores and glucose transporter. The aim of the present study is to evaluate the association of the SNPs of C5L2 gene with coronary artery disease (CAD) in a Chinese population.MethodsWe examined the role of the tagging single nucleotide polymorphisms (SNPs) of C5L2 gene for CAD using a case-control design. We determined the prevalence of C5L2 genotypes in 505 CAD patients and 469 age and sex-matched healthy control subjects of Han population.ResultsThere was significant difference in genotype distributions of rs2972607 and rs8112962 between CAD patients and control subjects. The rs2972607 was found to be associated with CAD in a dominant model (AA vs. AG + GG, P<0.001). Similarly, the rs8112962 was found to be associated with CAD in a dominant model (TT vs CT + CC, P=0.016). The difference remained statistically significant after multivariate adjustment (OR =1.401, 95% confidence interval [CI]:1.026~1.914, P=0.034; OR = 1.541, 95%CI:1.093~ 2.172, P=0.014; respectively).ConclusionThe results of this study indicate that both rs2972607 and rs8112962 of C5L2 gene are associated with CAD in a Han population of China.

What is the influence of complement factor C3 and lipid metabolism of adipose tissue on hepatic steatosis in mice?

NALFD (non-alcoholic fatty liver disease) represents a fatty liver whereby lipid accumulation (steatosis) occurs. In recent decades, the prevalence of NAFLD has dramatically increased. Activation of the complement system, which is an important subset of the immune system, and especially complement factor C3, may have a significant role in the progression of NAFLD. In this study is examined if there are, next to alterations in hepatic lipid metabolism, also alterations present in the lipid metabolism of adipose tissue. It appears that acylation stimulating protein (ASP) has an important role in linking the activation of complement and lipid metabolism of adipose tissue in NAFLD. In this study the following research question is stated: What is the influence of complement factor C3 and the lipid metabolism of adipose tissue on hepatic steatosis in mice? It is expected that wild type mice on a HFD diet will show the highest hepatic lipid accumulation. Furthermore the expression of some enzymes involved in lipid metabolism will be altered. Liver and adipose tissue from C3+/+ (n=17) and C3-/- (n=17) mice is used. The control group (n=12) received a chow diet and the experimental group (n=22) a high fat diet (HFD). The hepatic lipid accumulation and the expression of some enzymes, involved in the lipid metabolism of adipose tissue, are determined in these mice. The results, showed no significant differences in lipid accumulation between both mouse groups. The expression levels of the enzymes FASN, SCD1, PPARγ and DGAT1 were significantly different between the diets in one or both mouse groups. The expression of the enzymes HSL and DGAT1 were significantly higher in the C3+/+ mice compared to the C3-/- mice. It can be concluded from histological stainings and preliminary scoring results that hepatic lipid accumulation occurs the most in C3+/+ mice on a HFD. However it seems that lipids do not only accumulate by C3 activation, but also other mechanisms seems to play a role. It is assumed that in C3-/- mice the ASP pathway is disturbed, which will lead to an increased flux of fatty acids to the liver. In C3+/+ mice there is a higher adipose tissue lipolysis and lipogenesis present since the expression of HSL and DGAT were increased.

Progesterone and estrogen regulation of gene expression related to acylation stimulating protein production and function in ex vivo adipose tissue explant culture

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Nicotinic α7 receptor inhibits the acylation stimulating protein‑induced production of monocyte chemoattractant protein‑1 and keratinocyte‑derived chemokine in adipocytes by modulating the p38 kinase and nuclear factor‑κB signaling pathways.

Obesity is associated with chronic low-grade inflammation, which is characterized by increased infiltration of macrophages into adipose tissue. Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system, which constitutes a link between adipocytes and macrophages, and is involved in energy homeostasis and inflammation. The purpose of the present study was to preliminarily investigate in vitro, whether functional α7nAChR in adipocytes may suppress ASP-induced inflammation and determine the possible signaling mechanism. Studies have reported associations between the expression of α7 nicotinic acetylcholine receptor (α7nAChR) and obesity, insulin resistance and diabetes. Additionally, α7nAChRs are important peripheral mediators of chronic inflammation, which is a key contributor to health problems in obesity. The primary aim of the present study was to evaluate the impact of exogenous ASP and α7nAChR on macrophage infiltration in adipose tissue and to examine the potential underlying molecular mechanism. Western blot analysis revealed that recombinant ASP increased the expression levels of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte-derived chemokine (KC) by 3T3-L1 adipocytes. However, nicotine significantly inhibited the production of ASP-induced cytokines via the stimulation of α7nAChR. It was also found that α7nAChR inhibited the ASP-induced activation of p38 kinase and nuclear factor-κB (NF-κB), and the production of MCP-1 and KC. These data indicated that α7nAChR caused the inhibition of ASP-induced activation of p38 kinase and NF-κB to inhibit the production of MCP-1 and KC.

Low acylation stimulating protein levels are associated with cardiometabolic disorders-secondary to autoimmune activation?

Objective:We investigated the possible association of serum acylation stimulating protein (ASP) with cardiometabolic disorders and the evidence of autoimmune activation.Methods:Population-based randomly selected 1024 participants were cross-sectionally and prospectively analyzed. ASP concentrations were measured with a validated ELISA kit. Correlations were sought separately in subjects with no cardiometabolic disorders (n=427) designated as “healthy.”Results:ASP was positively correlated with total testosterone and inversely correlated with platelet activating factor (PAF), PAF-acetylhydrolase (AH), in each gender, and positively correlated in “healthy” men with lipoprotein [Lp](a) and apolipoprotein B. Correlations of ASP with PAF values ≥22 nmol/L were abolished, contrasted to a strongly inverse one in subjects with PAF <22 nmol/L. In linear regression analyses in the whole sample, ASP was inversely associated independently with PAF and PAF-AH and, in men, positively with Lp(a) and sex hormone-binding globulin. Prevalent and (at 2.0 years’ follow-up) incident metabolic syndrome (MetS, n=393), diabetes (n=154), and coronary heart disease (CHD, n=171) were analyzed by sex-, age-, and Lp(a)-adjusted logistic regression, using tertiles of ASP and PAF. The lower two (<42 nmol/L) ASP tertiles were a risk factor in combined sexes for MetS and diabetes. In women, incident CHD was predicted by either reduced or elevated ASP tertiles.Conclusion:Findings can be explained by the notion of operation of immune responses against both ASP and oxidized PAF-like lipids of Lp(a) to yield for “reduced” values and increased likelihood of cardiometabolic disorders.