Effects of Intravenous Infusion of Lipid-Free Apo A-I in Humans

Nanjee, M. Nazeem; Crouse, John R.; King, James M.; Hovorka, Roman; Rees, Stephen Edward; Carson, E.R.; Morgenthaler, J.‐J.; Lerch, P.; Miller, N. E.

doi:10.1161/01.atv.16.9.1203

Cited by 96 publications

(67 citation statements)

References 73 publications

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“…Interference of glucosamine with the assays reported is unlikely and has not been previously observed (8,9,11). The half-life of apoAI has been estimated to be 15-54 h (12). In individuals with diabetes and hypertriglyceridemia, the fractional catabolic rate of HDL and apoAI is increased (13).…”

Section: Results Andmentioning

confidence: 90%

The Effect of Glucosamine on Serum HDL Cholesterol and Apolipoprotein AI Levels in People With Diabetes

et al. 2007

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OBJECTIVE -Dietary and nutritional supplements are modulators of HDL cholesterol levels and production of apolipoprotein (apo) AI. Previously, in vitro treatment of hepatocyte cell lines with glucosamine increased apoAI production by stabilization of apoAI mRNA. The hypothesis is that the neutraceutical glucosamine, when given in conventional doses (1,500 mg/day) may increase apoAI and HDL cholesterol levels in subjects with diabetes and low HDL cholesterol.RESEARCH DESIGN AND METHODS -Twelve subjects (three men and nine women) with type 1 (n ϭ 2) and type 2 (n ϭ 10) diabetes, aged 55 Ϯ 12 years (mean Ϯ SD), who had low HDL cholesterol (1.03 Ϯ 0.20 mmol/l), were randomly assigned to a double-blind, placebo-controlled, cross-over trial of 500 mg glucosamine or placebo orally three times daily for 2 weeks, followed by a 4-week washout phase and a 2-week cross-over to the alternate therapy.RESULTS -Fasting serum glucose, fructosamine, and total cholesterol remained stable during the drug and placebo phases. Glucosamine had no significant effect after therapy on serum levels of HDL cholesterol (from baseline of 1.02 Ϯ 0.15 to 1.05 Ϯ 0.16 mmol/l compared with placebo from 1.04 Ϯ 0.21 to 1.06 Ϯ 0.16 mmol/l) nor in changes in apoAI levels (from baseline of 147 Ϯ 15 to 140 Ϯ 126 mg/dl with glucosamine and from 146 Ϯ 25 to 142 Ϯ 17 mg/dl with placebo).CONCLUSIONS -These observations suggest that glucosamine at commonly consumed doses does not have significant effects on glycemic control, lipid profile, or levels of apoAI in diabetic subjects after 2 weeks of supplementation. Diabetes Care 30:2800-2803, 2007I t is generally accepted that the mechanism of the increased risk of cardiovascular disease in diabetes is multifactorial (1). One such factor is probably the reduced serum levels of HDL in obese type 2 diabetic individuals (1,2). Dietary composition and nutritional supplements are important modulators of the HDL cholesterol level and the production of its main apolipoprotein (apo), namely, AI (3). Glucosamine, a popular nutritional supplement for treating arthritis, has been shown to alter apoAI production in hepatocyte cultures (4).Endogenous glucosamine is synthesized by the amidation of glucose-6-phosphate via the hexosamine biosynthetic pathway (5). Approximately 5% of glucose-6-phosphate is metabolized to N-acetylglucosamine by glutamine: fructose-6-phosphate amidotransferase. In addition, the extracellular glucosamine is transported into tissues and is subsequently phosphorylated to enter the hexosamine biosynthetic pathway. This pathway has been implicated in insulin resistance that may contribute to diabetes and cardiovascular diseases (5).Commercially available products containing glucosamine are used extensively as neutraceuticals in the treatment of arthritis and have been shown in large clinical trials to be safe in conventional doses (1,500 mg/day) (6,7). Parenteral administration of high doses of glucosamine (i.e., 5-30 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) may cause diabetes in experimental animals (8). Studies in he...

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Section: Results Andmentioning

confidence: 90%

The Effect of Glucosamine on Serum HDL Cholesterol and Apolipoprotein AI Levels in People With Diabetes

et al. 2007

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“…Purified human apoA-I has been safely infused into humans 39,40 with modest effects on plasma apoA-I and HDL cholesterol concentrations. Repeated infusions of recombinant apoA-I protein represents 1 possible approach to treatment of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice

et al. 1999

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Background-The ability of apolipoprotein (apo)A-I to induce regression of preexisting atherosclerotic lesions has not been determined, and a mouse model of atherosclerosis regression has not yet been reported. Methods and Results-LDL receptor-deficient mice were fed a western-type diet for 5 weeks to induce atherosclerotic lesions. A second-generation recombinant adenovirus encoding human apoA-I or a control adenovirus were injected intravenously in order to express apoA-I in the liver. Three days after injection, total apoA-I levels in mice injected with the apoA-I-expressing adenovirus were 216Ϯ16.0 mg/dL, compared with 68.0Ϯ3.0 mg/dL in control virus-injected mice (PϽ0.001). HDL cholesterol levels in mice injected with the AdhapoA-I vector 7 days after injection were 189Ϯ21.0 mg/dL, compared with 123Ϯ8.0 mg/dL in control virus-injected mice (PϽ0.02). Total and non-HDL cholesterol levels did not differ between the 2 groups. Atherosclerotic lesion area was quantified by en face analysis of the aorta and cross-sectional analysis of the aortic root. Compared with baseline mice, atherosclerosis progressed in mice injected with the control adenovirus. In contrast, in mice expressing apoA-I compared with baseline mice, total en face aortic lesion area was reduced by 70% and aortic root lesion was reduced by 46%. Expression of apoA-I was associated with a significant reduction in the fraction of lesions occupied by macrophages and macrophage-derived foam cells. Conclusions-Liver-directed gene transfer of human apoA-I resulted in significant regression of preexisting atherosclerotic lesions in LDL receptor-deficient mice as assessed by 2 independent methods. (Circulation. 1999;100:1816-1822.)

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“…The [ 3 H]LPS distribution among the major plasma lipoprotein classes was measured by ultracentrifugal flotation of undiluted plasma supernatants as described above or by size exclusion chromotography on a Superose 6 HR 10/30 column (Amersham Pharmacia Biotech) (37).…”

Section: Methodsmentioning

confidence: 99%

Plasma Lipoproteins Promote the Release of Bacterial Lipopolysaccharide from the Monocyte Cell Surface

Kitchens¹,

Wolfbauer

Albers

et al. 1999

Journal of Biological Chemistry

116

127

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Gram-negative bacterial lipopolysaccharide (LPS)1 (endotoxin) is one of the most potent and ubiquitous of the known bacterial signal molecules. Animals have sensitive mechanisms for recognizing the presence of LPS in tissues. Monocytes, macrophages, and neutrophils, which express the LPS binding receptor, CD14 (1, 2), and its signal transducer, Toll-like receptor-4 (3), are particularly sensitive to LPS (4). They respond by producing inflammatory mediators that amplify and diversify the LPS signal, triggering host defenses that wall off and destroy invading bacteria. For reasons that are not entirely clear, however, the response to LPS can also be harmful, resulting in severe sepsis, septic shock, and even death. Mechanisms that regulate responses to LPS are therefore likely to be very important for the host.HDL is the most abundant of the lipoproteins in human plasma and interstitial fluids. It can remove both phospholipids and unesterified cholesterol from cells (reviewed in Ref. 5), and HDL-mediated cellular cholesterol efflux and the subsequent delivery of HDL-cholesterol to the liver (reverse cholesterol transport) are thought to help protect animals from atherosclerosis. This study addresses another facet of the HDL particle: its ability to bind LPS and neutralize its biological activity. There is abundant evidence that HDL and other plasma lipoproteins play an important role in controlling host responses to LPS. Numerous studies have shown that complexes of LPS with HDL and other lipoproteins have little or no stimulatory activity, either in vitro or in vivo (6 -9), and there is now strong evidence that HDL and other lipoproteins can neutralize endotoxin in vivo (10 -17).Two plasma lipid transfer proteins, LPS-binding protein (LBP) (18,19) and phospholipid transfer protein (PLTP) (20), promote the binding of purified LPS to lipoproteins, whereas only LBP can facilitate LPS binding to CD14 on cell membranes (mCD14) or soluble CD14 (sCD14) in plasma (1,21,22). sCD14 can rapidly transfer LPS to mCD14 on cells (23), and it also facilitates the activation of cells that do not express mCD14 (24). Although sCD14 can also transfer LPS to HDL (19), it has been said to contribute very little to the movement of LPS to lipoproteins in whole plasma (25).In this study, we sought to determine whether HDL and plasma LPS transfer proteins could remove LPS from host cells. We found that HDL facilitates the release of cell-bound LPS, that sCD14 enhances this release, and that the removal of LPS from the cells attenuates proinflammatory responses. This new pathway of LPS traffic to lipoproteins may be important for regulating host responses to Gram-negative bacteria. These findings also raise the possibility that efflux of microbial ligands from macrophages to HDL contributes to the antiinflammatory potency of HDL in processes such as atherosclerosis. EXPERIMENTAL PROCEDURESCells and Reagents-Human monocytic THP-1 cells were cultured as described previously (26). CD14 expression was induced either by culturing the cells in 1...

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Effects of Intravenous Infusion of Lipid-Free Apo A-I in Humans

Cited by 96 publications

References 73 publications

The Effect of Glucosamine on Serum HDL Cholesterol and Apolipoprotein AI Levels in People With Diabetes

The Effect of Glucosamine on Serum HDL Cholesterol and Apolipoprotein AI Levels in People With Diabetes

Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice

Plasma Lipoproteins Promote the Release of Bacterial Lipopolysaccharide from the Monocyte Cell Surface

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