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Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an APOA5 mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5 -/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo., Competing Interests: Competing interests statement:S.G.Y. is on the scientific advisory board of Kyttaro; he has received consulting fees from Kyttaro and holds stock in that company. All authors from Eli Lilly & Co. own stock in the company.

Objective: The aim of this study was to compare serum leptin, apolipoprotein A1 (ApoA1), apolipoprotein J (ApoJ) and apolipoprotein H (ApoH) levels in males with obstructive sleep apnea and hypopnea syndrome (OSAHS) to those in healthy control subjects and to examine the possible relation between neurocognitive performance and these factors/serum markers in the subjects., Methods: In this observational, cross-sectional study, a full-night polysomnography and sensitive neuropsychological assessment were performed on 50 newly diagnosed Chinese male patients and 30 healthy subjects. Fasting blood samples were used to measure leptin and ApoA1, ApoH and ApoJ levels using ELISA., Results: Compared with normal control subjects, OSAHS patients have significantly lower levels of ApoA1 and higher levels of leptin, ApoH and ApoJ. After adjustment for age, years of education, body mass index (BMI) and apnea-hypopnea index, leptin and ApoA1 were associated with global cognitive function, and leptin level was positively correlated with inhibition reaction time. ApoJ was negatively correlated with visual reproduction and logical memory performance. Multiple regression analysis shows that from age, BMI, education year, biomarker levels and the parameters of PSG, only the variables of leptin and education year added to the prediction of the Montreal cognitive assessment score in a statistically significant way., Conclusions: Abnormal expression of leptin and apolipoproteins and poor performance on neuropsychological tests were observed in patients with OSAHS. There is also an association between serum leptin, ApoA1, and ApoJ levels and cognitive performance in the patients.

Triacylglycerol (TG) metabolism is tightly regulated to maintain a pool of TG within circulating lipoproteins that can be hydrolyzed in a tissue‐specific manner by lipoprotein lipase (LPL) to enable the delivery of fatty acids to adipose or oxidative tissues as needed. Elevated serum TG concentrations, which result from a deficiency of LPL activity or, more commonly, an imbalance in the regulation of tissue‐specific LPL activities, have been associated with an increased risk of atherosclerotic cardiovascular disease through multiple studies. Among the most critical LPL regulators are the angiopoietin‐like (ANGPTL) proteins ANGPTL3, ANGPTL4, and ANGPTL8, and a number of different apolipoproteins including apolipoprotein A5 (ApoA5), apolipoprotein C2 (ApoC2), and apolipoprotein C3 (ApoC3). These ANGPTLs and apolipoproteins work together to orchestrate LPL activity and therefore play pivotal roles in TG partitioning, hydrolysis, and utilization. This review summarizes the mechanisms of action, epidemiological findings, and genetic data most relevant to these ANGPTLs and apolipoproteins. The interplay between these important regulators of TG metabolism in both fasted and fed states is highlighted with a holistic view toward understanding key concepts and interactions. Strategies for developing safe and effective therapeutics to reduce circulating TG by selectively targeting these ANGPTLs and apolipoproteins are also discussed. [ABSTRACT FROM AUTHOR]

Sex difference is a risk factor for abdominal aortic aneurysm (AAA) formation yet the reason for male predominance remains unclear. Androgen and the androgen receptor (AR) influence the male sex difference, indicating that AR signaling may affect AAA development. Using angiotensin II–induced AAA in apolipoprotein E null mouse models (82.4% AAA incidence), we found that mice lacking AR failed to develop AAA and aorta had dramatically reduced macrophages infiltration and intact elastic fibers. These findings suggested that AR expression in endothelial cells, macrophages, or smooth muscle cells might play a role in AAA development. Selective knockout of AR in each of these cell types further demonstrated that mice lacking AR in macrophages (20% AAA incidence) or smooth muscle cells (12.5% AAA incidence) but not in endothelial cells (71.4% AAA incidence) had suppressed AAA development. Mechanism dissection showed that AR functioned through modulation of interleukin-1α (IL-1α) and transforming growth factor-β1 signals and by targeting AR with the AR degradation enhancer ASC-J9 led to significant suppression of AAA development. These results demonstrate the underlying mechanism by which AR influences AAA development is through IL-1α and transforming growth factor-β1, and provides a potential new therapy to suppress/prevent AAA by targeting AR with ASC-J9. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The efflux of cellular cholesterol mediated by apolipoprotein (apo)A-I and ATP-binding cassette transporter A1 (ABCA1) is a major pathway of reverse cholesterol transport. We investigated the effect of aspirin on this process. Methods: The expression levels of ABCA1 in RAW264.7 cells were determined using reverse transcription polymerase chain reaction and Western blot analysis. 3H-cholesterol efflux was measured by scintillation counting. Results: 0.5 mmol/l aspirin increased apoA-I-mediated cholesterol efflux and increased the expression of ABCA1. By increasing the dose of aspirin higher than 0.5 mmol/l, ABCA1 expression and function were significantly decreased. In cells transfected with a specific peroxisome proliferator-activated receptor (PPAR)-α small interfering RNA, the induction of ABCA1 expression and apoA-I-mediated 3H-cholesterol efflux by aspirin were substantially suppressed. Conclusions: The data demonstrate that low-dose aspirin increases ABCA1 expression via a PPAR-α-dependent mechanism and increases apoA-I-mediated cholesterol efflux. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Apolipoprotein D (apoD) is a lipoprotein-associated glycoprotein that is increased in the hippocampus and cerebrospinal fluid of patients with Alzheimer''s disease (AD), which implies that apoD might be involved in the pathogenesis of AD. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing techniques to screen all exons (1–5) and the flanking exon–intron boundaries of the apoD gene (APOD). Thirty subjects [15 sporadic AD (SAD) patients and 15 controls] were randomly selected and tested for APOD variations by direct sequencing. Two APOD polymorphisms (rs5952T/C and rs1568566C/T) were detected. We further investigated APOD polymorphisms in 256 SAD patients and 294 healthy subjects from a North Chinese population to investigate whether they affect the risk of SAD. Logistic analysis revealed that both rs5952 C and rs1568566 T alleles increase the risk of SAD [rs5952, adjusted odds ratio (OR) 1.817, 95% confidence interval (CI) 1.237–2.669, P =0.002; rs1568566, adjusted OR 1.563, 95% CI 1.060–2.306, P =0.024). The rs5952T–rs1568566C haplotype showed lower risk of SAD (OR 0.421, 95% CI 0.305–0.583, P =0.000). Case–control analysis revealed that the rs5952T–rs1568566C haplotype could serve as a novel defendant factor against SAD. APOD polymorphisms might play an important role in modifying SAD risk in some way. [Copyright &y& Elsevier]

Growing evidence suggests a synergistic and perhaps etiological relationship between vascular disease and Alzheimer's disease (AD), which is characterized by the progressive accumulation of amyloid-beta peptide (Abeta). Moreover, apolipoprotein E (ApoE) has also been shown to be associated with AD and cerebral ischemia. It seems that cerebral ischemia may play an important, both direct and indirect, role in the pathogenesis of AD. We investigated the expression and distribution of Abeta1-40, beta1-42 and ApoE in human hippocampus after cerebral ischemia in this study to determine the role of cerebral ischemia in Alzheimer's disease. Our study has demonstrated that the accumulation of both Abeta1-40 and beta1-42 were increased dramatically and consistently after cerebral ischemia. Neuronal ApoE immunoreactivity was also significantly increased in all ischemic groups compared with controls. The most likely stimulus for the increased Abeta1-40, Abeta1-42 and ApoE immunoreactivity in the CA1 and CA3 neurons is the ischemic conditions, and their upregulation, in turn, may partly explain the contribution of cerebral ischemia to the pathogenesis of AD. Therefore our observations provide a basis for establishing therapeutic strategies aimed at preventing ischemic insults and subsequent neurodegeneration in AD. [ABSTRACT FROM AUTHOR]