Impact of Sepsis on High-Density Lipoprotein Metabolism

Background: High-density lipoproteins (HDL) are thought to play a protective role in sepsis through several mechanisms, such as promotion of steroid synthesis, clearing bacterial toxins, protection of the endothelial barrier, and antioxidant/inflammatory activities. However, HDL levels decline rapidly during sepsis, but the contributing mechanisms are poorly understood.Methods/Aim: In the present study, we investigated enzymes involved in lipoprotein metabolism in sepsis and non-sepsis patients admitted to the intensive care unit (ICU).Results: In 53 ICU sepsis and 25 ICU non-sepsis patients, we observed significant differences in several enzymes involved in lipoprotein metabolism. Lecithin-cholesterol acyl transferase (LCAT) activity, LCAT concentration, and cholesteryl transfer protein (CETP) activity were significantly lower, whereas phospholipid transfer activity protein (PLTP) and endothelial lipase (EL) were significantly higher in sepsis patients compared to non-sepsis patients. In addition, serum amyloid A (SAA) levels were increased 10-fold in sepsis patients compared with non-sepsis patients. Furthermore, we found that LCAT activity was significantly associated with ICU and 28-day mortality whereas SAA levels, representing a strong inflammatory marker, did not associate with mortality outcomes.Conclusion: We provide novel data on the rapid and robust changes in HDL metabolism during sepsis. Our results clearly highlight the critical role of specific metabolic pathways and enzymes in sepsis pathophysiology that may lead to novel therapeutics.

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Abstract 541: The Molecular Interaction of Apolipoprotein A-I Containing High Density Lipoproteins with Lecithin: Cholesterol Acyl Transferase

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.541 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Allison Cooke ◽

John T Melchior ◽

Jamie C Morris ◽

Rong Huang ◽

W. Gray Jerome ◽

...

Keyword(s):

Protein Interactions ◽

Density Lipoprotein ◽

Negative Control ◽

High Density ◽

High Density Lipoproteins ◽

Acyl Transferase ◽

Lcat Activity ◽

Wild Type ◽

Cholesterol Acyl Transferase ◽

Hdl Function

The structure of apolipoprotein (apo)A-I on a high density lipoprotein (HDL) particle can elucidate the protein interactions and cardioprotective functions of HDL. This includes critical interactions with HDL modifying proteins like lecithin:cholesterol acyl transferase (LCAT) which performs a key function in reverse cholesterol transport by using apoA-I as a cofactor to esterify cholesterol. Data from our lab and others demonstrate that apoA-I molecules dimerize into an antiparallel stacked ring structure that encapsulates lipid in reconstituted (r)HDL particles. Cross-linking analysis of rHDL particles imply two possible registries: one with the fifth helical repeat of an apoA-I molecule adjacent to the fifth helical repeat of its antiparallel partner (5/5), and the other with the fifth helical repeat adjacent to the second helical repeat of its antiparallel partner (5/2). We hypothesized that apoA-I registry on rHDL can modulate LCAT activity. Site-directed cysteine mutagenesis was used to lock two apoA-I molecules into each of the aforementioned helical registries, and an intermediate registry created as a negative control. rHDL particles were generated using these dimerized mutants, and their ability to activate LCAT was determined. The 5/5 mutant demonstrated higher LCAT activity than wild-type rHDL particles while the 5/2 and intermediate mutants showed dramatically lower LCAT activity (p<0.001). To determine where LCAT interacts with apoA-I, rHDL containing wild-type apoA-I was cross-linked to LCAT. The majority of the cross-links were concentrated between S240 of LCAT and a region encompassing helices 4-6 of apoA-I. We propose that LCAT binds to a discontinuous epitope comprised of two apoA-I molecules in rHDL and that changes in this registry can alter LCAT function. These studies provide a basis for understanding how apoA-I structure may modulate the association and activity of a multitude of different HDL protein partners. This implicates apoA-I conformation as a target for altering HDL function in order to enhance the cardioprotective properties of HDL.

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Deactivation of the lipopolysaccharide antagonist eritoran (E5564) by high-density lipoprotein-associated apolipoproteins

Innate Immunity ◽

10.1177/1753425910394395 ◽

2011 ◽

Vol 18 (1) ◽

pp. 171-178 ◽

Cited By ~ 6

Author(s):

Jacklyn G Fleischer ◽

Dan Rossignol ◽

Gordon A Francis ◽

Teddy Chan ◽

Melvyn Lynn ◽

...

Keyword(s):

Whole Blood ◽

Lipid A ◽

Density Lipoprotein ◽

Antagonistic Activity ◽

High Density ◽

High Density Lipoproteins ◽

Amyloid A ◽

Tnf Α ◽

Signalling Cascade ◽

Pro Inflammatory Cytokines

Lipid A, the active moiety of LPS, exerts its effects through interaction with TLR4, triggering a signalling cascade that results in the release of pro-inflammatory cytokines. Eritoran is a lipid A analogue that competes with LPS for binding to TLR4; however, after intravenous administration, it undergoes a time-dependent deactivation as a consequence of binding to high-density lipoproteins (HDLs). The site of eritoran association with HDL remains unknown. Therefore the aim of this study was to determine if HDL-associated apolipoproteins A1, A2, serum amyloid A (SAA) and C1, inhibit the ability of eritoran to block LPS-induced TNF-α release from whole blood. Eritoran activity after LPS stimulation in human whole blood was assessed in the presence of reconstituted HDL (rHDL) containing different apos. In rHDL, the major apolipoproteins in both the healthy and septic state, A1 and SAA, caused a significant reduction in eritoran antagonistic activity and had a greater effect than minor apolipoproteins A2 and C1. Apolipoproteins associated with HDL are likely to facilitate eritoran deactivation. Apolipoproteins A1 and SAA should be of particular focus as they are the major apos found on HDL in both the healthy and septic state. Further evaluation of the physical association between apolipoproteins and eritoran should be explored.

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Human apolipoprotein A-I: structure determination and analysis of unusual diffraction characteristics

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s0907444999013128 ◽

1999 ◽

Vol 55 (12) ◽

pp. 2013-2021 ◽

Cited By ~ 2

Author(s):

David W. Borhani ◽

Jeffrey A. Engler ◽

Christie G. Brouillette

Keyword(s):

Structure Determination ◽

Density Lipoprotein ◽

High Density ◽

High Density Lipoproteins ◽

Major Protein ◽

Data Set ◽

Cholesterol Acyl Transferase ◽

Cell Parameters ◽

Human Apolipoprotein ◽

Apolipoprotein A

The crystallization and structure determination of recombinant human apolipoprotein A-I (apo A-I), the major protein component of high-density lipoprotein, is described. The fragment crystallized, residues 44–243 of native apo A-I [apo Δ(1–43)A-I], is very similar to intact native apo A-I in its ability to bind lipid, to be incorporated into high-density lipoproteins and to activate lecithin–cholesterol acyl transferase. Apo Δ(1–43)A-I crystallizes from 1.0–1.4 M sodium citrate pH 6.5–7.5 in space group P212121, with unit-cell parameters a = 97.47, b = 113.87, c = 196.19 Å (crystal form I). The crystals exhibit unusual diffraction intensity spikes and axial extinctions that are discussed in the context of the 4 Å crystal structure. When flash-cooled to 100 K, the crystals diffract synchrotron radiation to 3 Å resolution. Radiation sensitivity and crystal-to-crystal variation have hindered the assembly of a complete 3 Å data set.

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High-Density Lipoproteins and Serum Amyloid A (SAA)

Current Atherosclerosis Reports ◽

10.1007/s11883-020-00901-4 ◽

2021 ◽

Vol 23 (2) ◽

Author(s):

Nancy R. Webb

Keyword(s):

Serum Amyloid A ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Density Lipoprotein ◽

High Density ◽

Serum Amyloid ◽

High Density Lipoproteins ◽

Amyloid A

Abstract Purpose of Review Serum amyloid A (SAA) is a highly sensitive acute phase reactant that has been linked to a number of chronic inflammatory diseases. During a systemic inflammatory response, liver-derived SAA is primarily found on high-density lipoprotein (HDL). The purpose of this review is to discuss recent literature addressing the pathophysiological functions of SAA and the significance of its association with HDL. Recent Findings Studies in gene-targeted mice establish that SAA contributes to atherosclerosis and some metastatic cancers. Accumulating evidence indicates that the lipidation state of SAA profoundly affects its bioactivities, with lipid-poor, but not HDL-associated, SAA capable of inducing inflammatory responses in vitro and in vivo. Factors that modulate the equilibrium between lipid-free and HDL-associated SAA have been identified. Summary HDL may serve to limit SAA’s bioactivities in vivo. Understanding the factors leading to the release of systemic SAA from HDL may provide insights into chronic disease mechanisms.

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Prolonged bedrest reduces plasma high-density lipoprotein levels linked to markedly suppressed cholesterol efflux capacity

Scientific Reports ◽

10.1038/s41598-020-71921-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Athina Trakaki ◽

Hubert Scharnagl ◽

Markus Trieb ◽

Michael Holzer ◽

Helmut Hinghofer-Szalkay ◽

...

Keyword(s):

Cholesterol Efflux ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Oxidative Capacity ◽

High Density ◽

High Density Lipoproteins ◽

Cholesterol Efflux Capacity ◽

Vibration Exercise ◽

Amyloid A ◽

Hdl Function

Abstract Recent observations strongly connect high-density lipoproteins (HDL) function and levels with coronary heart disease outcomes and risk for infections and sepsis. To date, our knowledge of factors determining this connection is still very limited. The immobility associated with prolonged bedrest is detrimental to health, affecting several systems, including the cardiovascular, pulmonary, gastrointestinal, musculoskeletal and urinary. Effects of prolonged bedrest on the composition and functional properties of HDL remain elusive. We evaluated metrics of HDL composition and function in healthy male volunteers participating in a randomized, crossover head-down bedrest study. We observed that HDL cholesterol efflux capacity was profoundly decreased during bedrest, mediated by a bedrest associated reduction in plasma levels of HDL-cholesterol and major apolipoproteins (apo) apoA-I and apoA-II. Paraoxonase activity, plasma anti-oxidative capacity and the activities of lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein were not affected. No change was observed in the content of HDL-associated serum amyloid A, a sensitive marker of inflammation. Resistive vibration exercise countermeasure during bedrest did not correct impaired cholesterol efflux capacity and only tended to increase arylesterase activity of HDL-associated paraoxonase. In conclusion, prolonged bedrest reduces plasma HDL levels linked to markedly suppressed HDL cholesterol efflux capacity. Resistive vibration exercise during bedrest did not correct HDL levels and impaired cholesterol efflux capacity.

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Fasting plasma triacylglycerol concentrations predict adverse changes in lipoprotein metabolism after a normal meal

British Journal Of Nutrition ◽

10.1079/bjn19940013 ◽

1994 ◽

Vol 72 (1) ◽

pp. 101-109 ◽

Cited By ~ 16

Author(s):

Jennifer L. Potts ◽

Sandy M. Humphreys ◽

Simon W. Coppack ◽

Rachel M. Fisher ◽

Geoffrey F. Gibbons ◽

...

Keyword(s):

Daily Intake ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

High Density ◽

Cholesterol Concentration ◽

High Density Lipoproteins ◽

Very Low Density Lipoproteins ◽

Mixed Meal ◽

Fasting Plasma ◽

Plasma Triacylglycerol

The changes in lipoprotein metabolism which follow the ingestion of a large fat load have been well described. The hypothesis was tested that similar changes in lipoprotein metabolism would occur after a relatively normal meal. Plasma and lipoprotein triacylglycerol, cholesterol and apolipoprotein concentrations were determined in twenty subjects (ten female) given a mixed meal containing approximately one-third of the daily intake of major nutrients in the typical Western diet. Fasting plasma triacylglycerol concentrations (range 0.38–2.70 mm/l) and the postprandial rise in plasma triacylglycerol varied considerably between subjects and were significantly associated (P < 0.01). The rise in plasma triacylglycerol corresponded to marked increases in the triacylglycerol concentration of the triacylglycerol-rich lipoproteins (TRL; chylomicrons and very-low-density lipoproteins). TRL cholesterol also increased after the meal. An increase in high-density-lipoprotein (HDL)-triacylglycerol following the meal was accompanied by a decrease in HDL-cholesterol concentration, presumably due to the action of the cholesteryl-ester transfer protein. The increases in HDL-triacylglycerol and in TRL- cholesterol were correlated with the postprandial rise in triacylglycerol in the TRL (P < 0.01). We conclude that potentially adverse changes occur in both triacylglycerol-rich and high-density lipoproteins following a typical mixed meal, as they do after large fat loads. The changes are exaggerated in those subjects with greater fasting plasma triacylglycerol concentrations.

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Neutrophil association and degradation of normal and acute-phase high-density lipoprotein 3

Biochemical Journal ◽

10.1042/bj2480919 ◽

1987 ◽

Vol 248 (3) ◽

pp. 919-926 ◽

Cited By ~ 23

Author(s):

E G Shephard ◽

F C de Beer ◽

M C de Beer ◽

M S Jeenah ◽

G A Coetzee ◽

...

Keyword(s):

Acute Phase ◽

Density Lipoprotein ◽

High Density ◽

High Density Lipoproteins ◽

Human Neutrophils ◽

Amyloid A ◽

Apolipoprotein A ◽

Serum Amyloid A Protein ◽

Alpha 1 Antitrypsin

The interaction of normal and acute-phase high-density lipoproteins of the subclass 3 (N-HDL3 and AP-HDL3) with human neutrophils and the accompanying degradation of HDL3 apolipoproteins have been studied in vitro. The chemical composition of normal and acute-phase HDL3 was similar except that serum amyloid A protein (apo-SAA) was a major apolipoprotein in AP-HDL3 (approx. 30% of total apolipoproteins). 125I-labelled AP-HDL3 was degraded 5-10 times faster than 125I-labelled N-HDL3 during incubation with neutrophils or neutrophil-conditioned medium. Apo-SAA, like apolipoprotein A-II (apo-A-II), was more susceptible than apolipoprotein A-I (apo-A-I) to the action of proteases released from the cells. The amounts of cell-associated AP-HDL3 apolipoproteins at saturation were up to 2.8 times greater than N-HDL3 apolipoproteins; while apo-A-I was the major cell-associated apolipoprotein when N-HDL3 was bound, apo-SAA constituted 80% of the apolipoproteins bound in the case of AP-HDL3. The associated intact apo-SAA was mostly surface-bound as it was accessible to the action of exogenous trypsin. alpha 1-Antitrypsin-resistant (alpha 1-AT-resistant) cellular degradation of AP-HDL3 apolipoproteins also occurred; experiments in which pulse-chase labelling was performed or lysosomotropic agents were used indicated that insignificant intracellular degradation occurred which points to the involvement of cell-surface proteases in this degradation.

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Stimulation of apolipoprotein secretion in very-low-density and high-density lipoproteins from cultured rat hepatocytes by dexamethasone

Biochemical Journal ◽

10.1042/bj2710575 ◽

1990 ◽

Vol 271 (3) ◽

pp. 575-583 ◽

Cited By ~ 42

Author(s):

P Martin-Sanz ◽

J E Vance ◽

D N Brindley

Keyword(s):

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Rat Hepatocytes ◽

High Density ◽

High Density Lipoproteins ◽

Low Density ◽

Apo B ◽

Apo E ◽

The Masses

The effects of dexamethasone (a synthetic glucocorticoid) and insulin on the secretion of very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) were investigated. Rat hepatocytes in monolayer culture were preincubated for 15 h in the presence or absence of combinations of 100 nM-dexamethasone and 2 nM-, 10 nM- or 50 nM-insulin. Dexamethasone increased [3H]oleate incorporation into secreted triacylglycerol by 2.7-fold and the mass of triacylglycerol secreted by 1.5-fold. Insulin alone decreased these parameters and antagonized the effect of dexamethasone. Dexamethasone increased the secretion of [3H]leucine in apolipoprotein (apo) E, and in the large (BH) and small (BI) forms of apo B in VLDL by about 7.1-, 3.6- and 4.0-fold respectively. Insulin alone decreased the secretion of these 3H-labelled apolipoproteins in VLDL. However, 2 nM-insulin with dexamethasone increased the secretion of 3H-labelled apo BH and apo BL by a further 0.8- and 3.2-fold respectively; 50 nM-insulin decreased the secretions of apo E, apo BH and apo BL in VLDL. Similar effects for dexamethasone or insulin alone were also obtained for the masses of apo E and apo BL + H secreted in VLDL. Albumin secretion was not significantly altered by either dexamethasone or insulin alone, but in combination they stimulated by 2.1-2.6-fold. Insulin or dexamethasone alone had little effect on the secretion of apolipoproteins in the HDL fraction. However, dexamethasone plus 2 nM-insulin increased the incorporation of [3H]leucine into apo AI, apo AH plus apo C, apo AIV and apo E of HDL by about 1.8-, 1.6-, 1.7- and 2.0-fold respectively. The apo E in the bottom fraction represented about 69% of the total 3H-labelled apo E secreted. The responses in the total secretion of apo E from the hepatocytes resembled those seen in HDL. The interactions of insulin and dexamethasone are discussed in relation to the general regulation of lipoprotein metabolism, the development of hyperlipidaemias and the predisposition to premature atherosclerosis.

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High-Density Lipoproteins and Cardiovascular Disease: The Good, the Bad and the Future

Biomedicines ◽

10.3390/biomedicines9080857 ◽

2021 ◽

Vol 9 (8) ◽

pp. 857

Author(s):

Josep Julve ◽

Joan Carles Escolà-Gil

Keyword(s):

Cardiovascular Disease ◽

High Density Lipoprotein ◽

High Density Lipoprotein Cholesterol ◽

Density Lipoprotein ◽

Epidemiological Studies ◽

High Density ◽

High Density Lipoproteins ◽

Atherosclerotic Cardiovascular Disease ◽

Plasma High Density ◽

Low Levels

Epidemiological studies have shown that low levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with increased atherosclerotic cardiovascular disease (CVD) [...]

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