ApoE phenotype influences plasma ASP in hyperapoB subjects

Acylation stimulating protein (ASP) is increased in cardiovascular patients who often present with dyslipidemias. The aim of the present study was to examine the influence of apolipoprotein E (apoE) phenotype and lipids on ASP. Plasma ASP, lipids and apoE phenotype were measured in 407 subjects and separated according to the 75th percentile of apolipoprotein B (apoB) into a HyperapoB (HB) group (apoB=152±34 mg/dl, 117 men, 80 women) and a normal apoB (NB) group (apoB=88±19 mg/dl, 126 men, 84 women). Triglyceride (TG), cholesterol and LDL cholesterol were significantly increased in HB versus NB but there was no difference in age or body mass index (BMI). HB had increased ASP (42%>75th percentile, MEDIAN=48.4 nM, P<0.001) versus NB (36.5 nM). There was no difference in ASP in NB with any apoE3 variant (E3/3=41 nM, n=98; E3/4=46 nM, n=55; E3/2=50 nM, n=41), but ASP was increased in E2/2 (126 nM, n=9), and E4/4 (186 nM, n=5, P<0.001 ANOVA). In HB, ASP was increased in three apoE phenotypes: E2/4 (209 nM, n=6), E2/2 (135 nM, n=6) and E4/4 (189 nM, n=26), P<0.001 ANOVA relative to the other apoE phenotypes (E3/3=50 nM, n=102; E3/4=41 nM, n=40; E3/2=87 nM, n=17) with a wide range of values. By stepwise regression analysis, the best model that predicted ASP was: [plasma non-esterified fatty acid (NEFA)+TG+cholesterol], where r=0.407, P=0.001. These data suggest that apoE phenotype may potentially influence ASP, although primarily in rare apoE phenotypes.     

Acylation-stimulating protein precursor proteins in adipose tissue in human obesity

Recent reports have suggested a link between acylation-stimulating protein (ASP) and complement C3 with obesity, insulin resistance, coronary artery disease, and hyperlipidemia. Our aim was to examine the mRNA expression of C3 and other factors related to ASP production (such as factor B and adipsin) in adipose tissue. The influence of gender and obesity was examined in subcutaneous (SC) and omental (OM) tissues from 16 males and 16 females with body mass index (BMI) from 20 to 54 kg/m². The results demonstrate that factor B mRNA expression is higher in males than females in both SC and OM tissues. In female SC tissue, C3 and adipsin mRNA decrease with increasing BMI (r = 0.557, P = .025 and r = 0.717 P = .002, respectively), with no change in factor B. By contrast, in males there was a pronounced increase in C3, adipsin, and factor B in OM tissue with increasing BMI (r = 0.759 P = .001, r = 0.650 P = .006, and r = 0.568 P = .022, respectively). Of note, however, in both men and women there was a marked increase in the OM/SC ratio of C3 and adipsin with increasing BMI. These results suggest that in female SC adipose tissue, there is downregulation of factors related to ASP production in obesity, perhaps to limit further expansion of adipose tissue. In males, there is increased expression in OM tissue. In addition, relative OM/SC expression increases with obesity and these changes may contribute to the development of visceral adipose tissue.     

Reduced body weight, adipose tissue, and leptin levels despite increased energy intake in female mice lacking acylation-stimulating protein

Acylation-stimulating protein (ASP) is a potent lipogenic protein produced by adipocytes. In vitro studies have shown that ASP increases triglyceride synthesis and glucose transport in both murine and human adipocytes. Our initial study indicated that complement C3-deficient (-/-) mice (and, therefore, ASP deficient) demonstrated altered dietary postprandial triglyceride clearance. In the present study we examined the phenotype of female mice longitudinally on different diets. Female C3(-/-) mice on both low (10% of energy) and high (40% of energy) fat diets displayed an average reduction in total body weight of 10.1+/-0.5% (P < 0.0003, by ANOVA) compared with the C3(+/+) littermates. Reductions in white adipose tissue mass accounted for most of this weight difference (59% reduction; P < 0.01 on low fat diet). Plasma leptin levels were significantly reduced in C3(-/-) mice on both high (P < 0.001) and low fat diets (P < 0.01). This reduction was significant even after adjusting for the reduced body weight and body fat (P < 0.001). Leptin reductions in the C3(-/-) were greater on the high fat diet and were associated with increased food intake (18+/-2% increase; P < 0.001). Furthermore, there was a decrease in basal glucose levels and basal insulin levels [12.8% decrease in glucose at 14 weeks (HF; P < 0.05) and 41% decrease in insulin at 26 weeks (HF; P < 0.05)]. These in vivo experiments demonstrate that female mice lacking ASP have marked alterations of body weight, adiposity, plasma leptin, and plasma insulin levels. Decreased adiposity and leptin levels occurred in the ASP-deficient animals despite increased energy intake, suggesting that energy expenditure was elevated in these animals. Thus, ASP appears to have an important role in the regulation of energy balance in mice.     

Combining cell and gene therapy to advance cardiac regeneration

Introduction: The characterization of multipotent endogenous cardiac stem cells (eCSCs) and the breakthroughs of somatic cell reprogramming to boost cardiomyocyte replacement have fostered the prospect of achieving functional heart repair/regeneration.

Areas covered: Allogeneic CSC therapy through its paracrine stimulation of the endogenous resident reparative/regenerative process produces functional meaningful myocardial regeneration in pre-clinical porcine myocardial infarction models and is currently tested in the first-in-man human trial. The in vivo test of somatic reprogramming and cardioregenerative non-coding RNAs revived the interest in gene therapy for myocardial regeneration. The latter, together with the advent of genome editing, has prompted most recent efforts to produce genetically-modified allogeneic CSCs that secrete cardioregenerative factors to optimize effective myocardial repair.

Expert opinion: The current war against heart failure epidemics in western countries seeks to find effective treatments to set back the failing hearts prolonging human lifespan. Off-the-shelf allogeneic-genetically-modified CSCs producing regenerative agents are a novel and evolving therapy set to be affordable, safe, effective and available at all times for myocardial regeneration to either prevent or treat heart failure.     

2型糖尿病和冠心病患者血浆促酰化蛋白水平的研究

目的:测定2型糖尿病和冠心病患者血浆促酰化蛋白(ASP)水平,探讨血浆ASP与体重指数、血脂的相关关系.方法:实验分3组:正常对照组47例、糖尿病组63例、冠心病组62例,记录每例被试对象的年龄、性别、身高、体重、血压,并计算体重指数(BMI).酶联免疫吸附分析法(ELISA)检测血浆ASP浓度,免疫比浊法检测血脂等生化指标.结果:①糖尿病组、冠心病组ASP水平明显高于正常对照组(P＜0.05).②ASP与体重指数、收缩压、舒张压、总胆固醇、甘油三酯、低密度脂蛋白胆固醇、载脂蛋白B100呈显著正相关(分别为r=0.32,P＜0.01;r=0.24,P＜0.01;r=0.19,P＜0.01;r=0.35,P＜0.01;r=0.10,P＜0.05;r=0.29,P＜0.01;r=0.32,P＜0.01).③多元逐步回归分析:载脂蛋白B100、体重指数、高密度脂蛋白胆固醇和舒张压最终进入方程,它们是影响血浆ASP水平的重要因素,其中载脂蛋白B100的作用最大.结论:ASP参与了糖尿病和冠心病患者脂质代谢紊乱的发生,血浆ASP水平可能作为估价糖尿病患者发生心血管疾病危险性的新指标.     

Reduced adipose tissue triglyceride synthesis and increased muscle fatty acid oxidation in C5L2 knockout mice

Activation of C5L2, a G-protein-coupled receptor, by acylation-stimulating protein/complement C3adesArg (ASP/C3adesArg) has been shown to stimulate triglyceride (TG) synthesis in both mature adipocytes and preadipocytes. ASP is an adipocyte-derived hormone that acts by increasing diacylglycerol acyltransferase activity and glucose transport. ASP-deficient mice (C3KO, precursor protein) are lean, display delayed postprandial TG clearance, increased food intake, and increased energy expenditure. The present study shows that C5L2KO mice on a low fat diet are hyperphagic (~60% increase in total food intake) yet maintain the same body weight and adipose tissue mass as wild-type (WT) controls. However, on a high fat diet, average adipocyte size and adipose tissue TG/DNA content were significantly reduced and postprandial TG clearance was delayed in C5L2KO. Adipose tissue TG synthesis (WT: 47.2 +/- 5.6 versus C5L2KO: 7.8 +/- 1.8 pmol/microg protein, P < 0.001), TG lipolysis (WT: 227.6 +/- 36.4 versus C5L2KO: 45.8 +/- 5.0 nmol/microg protein, P < 0.001), and fatty acid re-esterification (WT: 85.3 +/- 2.4% versus C5L2KO: 59.5 +/- 6.8%, P < 0.001) were significantly reduced in C5L2KO mice. Indirect calorimetry measurements revealed C5L2KO mice have unchanged oxygen consumption levels yet reduced respiratory quotient value, suggesting preferential fatty acid utilization over carbohydrate. In agreement, fatty acid oxidation was elevated in heart and skeletal muscle tissue in C5L2KO mice and skeletal muscle levels of uncoupling protein 3 (425.5 +/- 86.3%, P < 0.0001), CD36 (277.6 +/- 49.5%, P < 0.05), cytochrome c (252.6 +/- 33.9%, P < 0.05), and phospho-acetyl CoA carboxylase (118.4 +/- 9.3%, P < 0.05) were significantly increased in C5L2KO mice versus WT (100%). The study shows that in response to reduced TG storage in white adipose tissue, C5L2KO mice have developed a compensatory mechanism of increased muscle fat oxidation.     

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.     

Hyperapobetalipoproteinemia: the major dyslipoproteinemia in patients with chronic renal failure treated with chronic ambulatory peritoneal dialysis

In the present study, plasma cholesterol, triglyceride, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, and the major protein in LDL, apoB, were measured in 28 patients with chronic renal failure treated with hemodialysis and in 28 patients with chronic renal failure treated with chronic ambulatory peritoneal dialysis (CAPD). Elevated plasma triglycerides and reduced HDL cholesterol were frequent in both the hemodialysis and CAPD patients. However LDL levels were significantly higher in the CAPD patients as evident both by LDL cholesterol and LDL apoB. Even so, only one of the CAPD patients was hypercholesterolemic whereas 14 (or 50%) had hyperapobetalipoproteinemia (HyperapoB). Insulin-dependent diabetes was more frequent in the CAPD group but only 2 of the 9 insulin-dependent diabetics in this group had HyperapoB, and therefore, diabetes mellitus cannot account for the difference between the 2 groups. Thus HyperapoB appears to be a prevalent dyslipoproteinemia in CAPD patients and as such might be another factor which places CAPD patients at particularly increased risk of atherosclerosis.