High‐density Lipoprotein Apolipoprotein A‐I Kinetics in Obesity

Objective: Low plasma concentrations of high‐density lipoprotein (HDL)‐cholesterol and apolipoprotein A‐I (apoA‐I) are independent predictors of coronary artery disease and are often associated with obesity and the metabolic syndrome. However, the underlying kinetic determinants of HDL metabolism are not well understood. Research Methods and Procedures: We pooled data from 13 stable isotope studies to investigate the kinetic determinants of apoA‐I concentrations in lean and overweight—obese individuals. We also examined the associations of HDL kinetics with age, sex, BMI, fasting plasma glucose, fasting insulin, Homeostasis Model Assessment score, and concentrations of apoA‐I, triglycerides, HDL‐cholesterol and low‐density lipoprotein‐cholesterol. Results: Compared with lean individuals, overweight—obese individuals had significantly higher HDL apoA‐I fractional catabolic rate (0.21 ± 0.01 vs. 0.33 ± 0.01 pools/d; p < 0.001) and production rate (PR; 11.3 ± 4.4 vs. 15.8 ± 2.77 mg/kg per day; p = 0.001). In the lean group, HDL apoA‐I PR was significantly associated with apoA‐I concentration (r = 0.455, p = 0.004), whereas in the overweight—obese group, both HDL apoA‐I fractional catabolic rate (r = ?0.396, p = 0.050) and HDL apoA‐I PR (r = 0.399, p = 0.048) were significantly associated with apoA‐I concentration. After adjustment for fasting insulin or Homeostasis Model Assessment score, HDL apoA‐I PR was an independent predictor of apoA‐I concentration. Discussion: In overweight—obese subjects, hypercatabolism of apoA‐I is paralleled by an increased production of apoA‐I, with HDL apoA‐I PR being the stronger determinant of apoA‐I concentration. This could have therapeutic implications for the management of dyslipidemia in individuals with low plasma HDL‐cholesterol.     

Fat Compartments and Apolipoprotein B‐100 Kinetics in Overweight‐Obese Men

Objective: To examine the association between the kinetics of very‐low‐density‐lipoprotein (VLDL)‐apolipoprotein B‐100 (apoB) and intraperitoneal, retroperitoneal, subcutaneous abdominal, and total adipose tissue masses (IPATM, RPATM, SAATM, and TATM, respectively) in overweight/obese men. Research Methods and Procedures: Hepatic secretion of VLDL was measured using an intravenous infusion of 1‐[¹³C]‐leucine in 51 men with a wide range of body mass index (25.1 to 42.2 kg/m²). Isotopic enrichment of VLDL‐apoB was measured using gas chromatography‐mass spectrometry and a multicompartmental model used to estimate VLDL‐apoB metabolic parameters. IPATM, RPATM, and SAATM (kilograms) were quantified between T11 and S1 using magnetic resonance imaging; TATM (kilograms) was determined using bioelectrical impedance. Insulin resistance was estimated by homeostasis model assessment (HOMA) score. Results: In stepwise regression, IPATM was the best predictor of hepatic secretion of VLDL‐apoB (r = 0.390, p < 0.005) and TATM was the best predictor of VLDL‐apoB fractional catabolic rate (r = 0.282, p < 0.05). IPATM remained significantly associated with VLDL‐apoB secretion after adjusting for TATM or HOMA score (r = 0.360, p < 0.01 and r = 0.310, p < 0.05, respectively). This association was also independent of age, dietary intake, and body mass index. None of the fat compartments were significantly associated with the fractional catabolic rate of VLDL‐apoB after adjusting for HOMA score. Discussion: In overweight/obese men, the quantity of both IPATM and TATM determine the kinetics of VLDL‐apoB. The effect of IPATM on VLDL‐apoB secretion is independent of both total fat mass and the degree of insulin resistance.     

Apolipoprotein A‐II Polymorphism and Visceral Adiposity in African‐American and White Women

To determine the association between the ?265 T to C substitution in the apolipoprotein A‐II (APOA‐II) gene and levels of visceral adipose tissue (VAT) in a group of premenopausal African‐American and white women, we genotyped 237 women (115 African‐American and 122 white) for this polymorphism. Body composition was assessed by DXA, and VAT was determined from a single computed tomography scan. In addition to VAT, we examined the association between the polymorphism and other phenotypes (total body fat, total abdominal adipose tissue, and subcutaneous abdominal adipose tissue). The mutant C allele in the APOA‐II gene was less frequent in African‐American compared with white women, 23% vs. 36%, respectively (p < 0.01). VAT was significantly higher in carriers of the C allele compared with noncarriers after adjustment for total body fat (p < 0.05). When separate analyses by ethnic group were conducted, the association between the polymorphism and VAT was observed in white (p < 0.05) but not African‐American (p = 0.57) women. There was no association between the polymorphism and the other phenotypes. These results indicate a significant association between the T265C APOA‐II polymorphism and levels of VAT in premenopausal women. This association is present in white but not African‐American women.     

Apolipoprotein A‐I peptide models as probes to formulate potential inhibitors of the low‐density lipoprotein oxidation

Apolipoprotein A‐I (apoA‐I), which constitutes the principal protein component of high‐density lipoprotein, is responsible for its major antiatherogenic functions. Aiming at contributing to the development of potent inhibitors of low‐density lipoprotein (LDL) peptide models of helices 4,6 and 9,10 of apoA‐I were designed and synthesized. Specific amino acid substitutions, resulting in transformation of the original helix class A and Y to G according to the Schiffer and Edmundson helical wheel representation, were introduced in order to validate the contribution of these modifications in the inhibitory activity of the synthesized peptide models against the LDL oxidation. The role of Met at positions 112 (helix 4) and 148 (helix 6) as oxidant scavenger was also investigated. The helical characteristics of all the peptide models were studied by CD in membrane‐mimicking microenvironments and compared with the original helices. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Apolipoprotein A‐I possesses an anti‐obesity effect associated with increase of energy expenditure and up‐regulation of UCP1 in brown fat

Apolipoprotein A‐I (ApoA‐I) is the most abundant protein constituent of high‐density lipoprotein (HDL). Reduced plasma HDL and ApoA‐I levels have been found to be associated with obesity and metabolic syndrome in human beings. However, whether or not ApoA‐I has a direct effect on obesity is largely unknown. Here we analysed the anti‐obesity effect of ApoA‐I using two mouse models, a transgenic mouse with overexpression of ApoA‐I and the mice administered with an ApoA‐I mimetic peptide D‐4F. The mice were induced to develop obesity by feeding with high fat diet. Both ApoA‐I overexpression and D‐4F treatment could significantly reduce white fat mass and slightly improve insulin sensitivity in the mice. Metabolic analyses revealed that ApoA‐I overexpression and D‐4F treatment enhanced energy expenditure in the mice. The mRNA level of uncoupling protein (UCP)1 in brown fat tissue was elevated by ApoA‐I transgenic mice. ApoA‐I and D‐4F treatment was able to increase UCP1 mRNA and protein levels as well as to stimulate AMP‐activated protein kinase (AMPK) phosphorylation in brown adipocytes in culture. Taken together, our results reveal that ApoA‐I has an anti‐obesity effect in the mouse and such effect is associated with increases in energy expenditure and UCP1 expression in the brown fat tissue.     

Apolipoprotein AI tertiary structures determine stability and phospholipid‐binding activity of discoidal high‐density lipoprotein particles of different sizes

Human high‐density lipoprotein (HDL) plays a key role in the reverse cholesterol transport pathway that delivers excess cholesterol back to the liver for clearance. In vivo, HDL particles vary in size, shape and biological function. The discoidal HDL is a 140–240 kDa, disk‐shaped intermediate of mature HDL. During mature spherical HDL formation, discoidal HDLs play a key role in loading cholesterol ester onto the HDL particles by activating the enzyme, lecithin:cholesterol acyltransferase (LCAT). One of the major problems for high‐resolution structural studies of discoidal HDL is the difficulty in obtaining pure and, foremost, homogenous sample. We demonstrate here that the commonly used cholate dialysis method for discoidal HDL preparation usually contains 5–10% lipid‐poor apoAI that significantly interferes with the high‐resolution structural analysis of discoidal HDL using biophysical methods. Using an ultracentrifugation method, we quickly removed lipid‐poor apoAI. We also purified discoidal reconstituted HDL (rHDL) into two pure discoidal HDL species of different sizes that are amendable for high‐resolution structural studies. A small rHDL has a diameter of 7.6 nm, and a large rHDL has a diameter of 9.8 nm. We show that these two different sizes of discoidal HDL particles display different stability and phospholipid‐binding activity. Interestingly, these property/functional differences are independent from the apoAI α‐helical secondary structure, but are determined by the tertiary structural difference of apoAI on different discoidal rHDL particles, as evidenced by two‐dimensional NMR and negative stain electron microscopy data. Our result further provides the first high‐resolution NMR data, demonstrating a promise of structural determination of discoidal HDL at atomic resolution using a combination of NMR and other biophysical techniques.     

Plasma Markers of Cholesterol Homeostasis and Apolipoprotein B‐100 Kinetics in the Metabolic Syndrome

Objective: The metabolic syndrome is characterized by defective hepatic apolipoprotein B‐100 (apoB) metabolism. Hepato‐intestinal cholesterol metabolism may contribute to this abnormality. Research Methods and Procedures: We examined the association of cholesterol absorption and synthesis with the kinetics of apoB in 35 obese subjects with the metabolic syndrome. Plasma ratios of campesterol and lathosterol to cholesterol were used to estimate cholesterol absorption and synthesis, respectively. Very‐low‐density lipoprotein (VLDL), intermediate‐density lipoprotein (IDL), and low‐density lipoprotein apoB kinetics were studied using stable isotopy and mass spectrometry. Kinetic parameters were derived using multicompartmental modeling. Results: Compared with controls, the obese subjects had significantly lower plasma ratios of campesterol, but higher plasma ratios of lathosterol (p < 0.05 in both). This was associated with elevated VLDL‐apoB secretion rate (p < 0.05) and delayed fractional catabolism of IDL and low‐density lipoprotein‐apoB (p < 0.01). In the obese group, plasma ratios of campesterol correlated inversely with VLDL‐apoB secretion (r = ?0.359, p < 0.05), VLDL‐apoB (r = ?0.513, p < 0.01) and IDL‐apoB (r = ?0.511, p < 0.01) pool size, and plasma lathosterol ratio (r = ?0.366, p < 0.05). Subjects with low cholesterol absorption had significantly higher VLDL‐apoB secretion, VLDL‐apoB and IDL‐apoB pool size, and plasma lathosterol ratio (p < 0.05 in both) than those with high cholesterol absorption. Discussion: Subjects with the metabolic syndrome have oversecretion of VLDL‐apoB and decreased catabolism of apoB‐containing particles and low absorption and high synthesis rates of cholesterol. These changes in cholesterol homeostasis may contribute to the kinetic defects in apoB metabolism in the metabolic syndrome.     

Association between Low‐Molecular Weight Apolipoprotein(a) Isoforms and Obesity in Italian Women

Objective: Low‐molecular weight (MW) apolipoprotein(a) [apo(a)] isoforms are closely associated with an increased incidence of atherothrombotic disease, prevalence of which is higher in obese individuals, particularly in women. The hypothesis of this study was to assess whether there are differences in the distribution of apo(a) phenotypes between obese patients and healthy controls. Research Methods and Procedures: One hundred three obese Italian women (BMI ≥ 30.0 kg/m²) were enrolled in the study, and apo(a) phenotyping was performed in all subjects. The prevalence of low‐MW apo(a) isoforms, detected in plasma samples of our obese women, was compared with that found in a control group of 84 normal‐weight, never‐obese (BMI < 25.0 kg/m²), age‐matched women. Results: The distribution of apo(a) isoforms in the population of obese women was significantly different from that found in normal‐weight female subjects. In particular, the percentage of subjects in the obese group with at least one apo(a) isoform of low MW was significantly higher than that in the control group (51.4% vs. 32.1%, p = 0.0079). Discussion: Our results seem to suggest the possibility that small‐sized apo(a) isoforms may be used together with other traditional risk factors to better assess the overall predisposition to atherothrombotic disease in obese women.     

Apolipoprotein E Attenuates β-Amyloid-Induced Astrocyte Activation

Abstract: A common feature of Alzheimer's disease pathology is an abundance of activated glia, indicative of an inflammatory reaction in the brain. The relationship between glial activation and neurodegeneration is not known, although several cytokines and inflammatory mediators produced by activated glia have the potential to initiate or exacerbate the progression of neuropathology. As β-amyloid (Aβ) is one of several stimuli that can activate glia, it is important to determine how Aβ-induced glial activation is influenced by other proteins present in the plaque, such as apolipoprotein E (apoE). We examined the effect of native preparations of apoE on activation of rat cortical astrocyte cultures by Aβ1–42. The apoE source was conditioned medium from human embryonic kidney 293 cells stably transfected with human apoE3 or apoE4 cDNA. By morphological criteria, apoE inhibited Aβ-induced astrocyte activation in three experimental paradigms: apoE pretreatment blocked subsequent Aβ-induced activation, Aβ aged in the presence of apoE did not activate astrocytes, and apoE addition to activated astrocytes transiently reversed the activated phenotype. No apoE isoform selectivity was observed. The effect of apoE appears to be specific to Aβ, as apoE did not attenuate cyclic AMP-induced astrocyte activation. These data suggest that apoE may modulate the ability of Aβ to induce inflammatory responses in the brain.     

载脂蛋白M

载脂蛋白M(apoM)是一类在血液中主要与高密度脂蛋白（HDL）结合的载脂蛋白,呈组织特异性表达且有着众多生物学功能.体内外多种因素可从转录或转录后水平对其表达进行调控:肝细胞核因子-1α,4α（HNF-1α,4α）、肝受体同系物-1（LRH-1）、叉头框转录因子a2（Foxa2）、血小板活化因子（PAF）等可上调其表达;肝X受体（LXR）、维甲酸X受体（RXR）、法尼酯X受体（FXR）、小异源二聚体-1(SHP-1)以及绝大多数细胞因子可下调其表达,具体调节机制复杂. 结构上,apoM含有一个特征性的疏水性信号肽,可结合1 磷酸鞘氨醇（S1P）等小的生物活性脂,以此介导多项生命活动. 功能上,apoM能促进preβ-HDL的生成,并提高其一系列抗动脉粥样硬化的生物活性,如胆固醇逆向转运、抗炎、以及低密度脂蛋白（LDL）的抗氧化等.在一些糖尿病病人体内,apoM的含量也显著降低,而apoM含量的提高可以降低血糖含量,增加胰岛素分泌以及改善胰岛素抵抗,不少学者将其视为该病发生发展的一项预测指标.本文就近年来对apoM的生物学特性,特别是其表达调控机制和功能的研究进展进行综述.     

Apolipoprotein D

Apolipoprotein D (apoD) is a 29-kDa glycoprotein that is primarily associated with high density lipoproteins in human plasma. It is an atypical apolipoprotein and, based on its primary structure, apoD is predicted to be a member of the lipocalin family. Lipocalins adopt a beta-barrel tertiary structure and transport small hydrophobic ligands. Although apoD can bind cholesterol, progesterone, pregnenolone, bilirubin and arachidonic acid, it is unclear if any, or all of these, represent its physiological ligands. The apoD gene is expressed in many tissues, with high levels of expression in spleen, testes and brain. ApoD is present at high concentrations in the cyst fluid of women with gross cystic disease of the breast, a condition associated with increased risk of breast cancer. It also accumulates at sites of regenerating peripheral nerves and in the cerebrospinal fluid of patients with neurodegenerative conditions, such as Alzheimer's disease. ApoD may, therefore, participate in maintenance and repair within the central and peripheral nervous systems. While its role in metabolism has yet to be defined, apoD is likely to be a multi-ligand, multi-functional transporter. It could transport a ligand from one cell to another within an organ, scavenge a ligand within an organ for transport to the blood or could transport a ligand from the circulation to specific cells within a tissue.