ARTICLE IN PRESS

Clinical Nutrition (2005) 24, 16 31

http:/ /intl.elsevierhealth.com/journals/clnu

REVIEW

Dyslipidemia and inammation: an evolutionary conserved mechanism

Eduardo Esteve, Wifredo Ricart, Jose Manuel Ferna ndez-Real
Seccio n de Diabetes, Endocrinolog a y Nutricio n, Hospital Universitario de Girona Dr Josep Trueta, Avenida de Francia s/n, 17007 Girona, Spain
Received 16 August 2004; accepted 16 August 2004

KEYWORDS
Dyslipemia; Inammation; Cytokines; Atherosclerosis

Summary Inammation leads to changes in lipid metabolism aimed at decreasing the toxicity of a variety of harmful agents and tissue repair by redistributing nutrients to cells involved in host defence. Acute phase response, mediated by cytokines, preserves the host from acute injury. When this inammation becomes chronic, it might lead to chronic disorders as atherosclerosis and the metabolic syndrome. The activation of the inammatory cascade will induce a decrease in HDLcholesterol (HDL-C), with impairment in reverse cholesterol transport, and parallel changes in apolipoproteins, enzymes, anti-oxidant capacity and ATP binding cassette A1-dependent efux. This decrease in HDL-C and phospholipids could stimulate compensatory changes, as synthesis and accumulation of phospholipid-rich VLDL which binds bacterial products and other toxic substances, resulting in hypertriglyceridemia. The nal consequence is an increased accumulation of cholesterol in cells. When the compensatory response (inammation) is not able to repair injury, it turns into a harmful reaction, and the lipid changes will become chronic, either by repeated or overwhelming stimulus, enhancing the formation of atherosclerotic lesions. Thus, the classical lipid changes associated with the metabolic syndrome (increased triglycerides and decreased HDL-C) may be envisioned as a highly conserved evolutionary response aimed at tissue repair. Under this assumption, the problem is not the response but the persistence of the stimulus. & 2004 Elsevier Ltd. All rights reserved.

Corresponding author. Tel.:+34-972940200; fax:+34-972940270.

E-mail address: uden.jmfernandezreal@htrueta.scs.es (J.M. Ferna ndez-Real). 0261-5614/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.clnu.2004.08.004

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Dyslipidemia and inammation
Contents Changes in HDL lipoprotein during inammation . HDL particles and inammation . . . . . . . . Changes in reverse cholesterol transport . . . Changes in HDL-associated apolipoproteins . Changes in HDL-associated enzymes . . . . . . Changes in other HDL-associated proteins . . Changes in phospholipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 18 18 19 19 20 20 21 21 21 21 22 22 23 23 23

17

Changes in VLDL lipoprotein and TGs during inammation. TGs and inammation. . . . . . . . . . . . . . . . . . . . . Pathophysiology of TG disturbances . . . . . . . . . . . . Increased lipoprotein production . . . . . . . . . . . Decreased lipoprotein clearance . . . . . . . . . . .

Changes in LDL lipoprotein and cholesterol during inammation . LDL-C and inammation . . . . . . . . . . . . . . . . . . . . . . . Changes in LDL-C clearance during infection . . . . . . . . . . LDL size and oxidative modications during inammation . .

Lipoprotein(a), inammation and tissue repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Fatty acid and cholesterol transport in plasma lipoproteins evolved in the context of an open circulatory system in which lipoprotein particles are secreted directly into the blood and have ready access to cells in various tissues. In higher vertebrates and humans, with closed capillary beds, hydrolysis of triglycerides (TGs) at capillary surfaces is required for efcient uptake of their component fatty acids into cells. Likewise, hydrolysis of cellular TGs in cells of adipose tissue precedes mobilization of the fatty acids and permits large amounts to be transported in the blood.1 Infection and inammation trigger a variety of changes known as acute-phase response (APR). The characteristic disturbances of lipid metabolism found during APR are increased serum TG concentration and decreased HDL-cholesterol (HDL-C). During APR, changes in total cholesterol (TC) and LDL-cholesterol (LDL-C) may also occur. While in rodents and rabbits TC and LDL-C are raised during infection, in primates and humans the opposite is usually observed. This APR protects from tissue injury and facilitates the mechanisms of reparation. However, a wide range of disturbances in lipid metabolism occurs. These changes, which are mediated by cytokines, are aimed to decrease the toxicity of a variety of harmful biological and chemical agents and serve to redistribute nutrients

to cells important in host defense.2 These alterations in lipid metabolism during inammation and infection are aimed to: (1) Redirect lipoproteins to sites of injury, as shown with cytokine-induced serum amyloid A (SAA) from HDL particles.3 (2) Increase lipid delivery to immune cells involved in host defence.4 (3) Bind microbial products.5,6 In this sense, lipoproteins bind the bioactive lipid A portion of lipopolysaccharide (LPS) and prevent it from stimulating monocytes, macrophages and other cells, protecting the host from the toxic effects caused by these substances.711 Lipoproteinbound LPS is cleared from the circulation mainly by the liver and excreted into the bile.12,13 In in vivo experimental models, raising plasma lipoprotein levels decrease stimulatory effects of LPS and increase host survival during endotoxemia or bacterial infection.14,15 Apolipoprotein E (apoE) is also able to bind LPS, and, interestingly, an increased uptake of apoELPSrich particles by hepatic LDL receptors has been described.16,17 (4) Bind viruses and urate crystals, blocking their cytotoxic effects and reducing the inammatory response.18,19 (5) Induce lysis of some parasites as Trypanosoma bruceii.20

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18 Despite these initial benecial effects, lipid disturbances linked to chronic inammation will undoubtedly participate in the increased cardiovascular risk associated with hyperlipidemia. Lipid disturbances as hypercholesterolemia and low HDLC levels are major cardiovascular risk factors. Lipid accumulation in macrophages results in the formation of lipid foam cells, which accumulate within the arterial wall to form fatty streaks, an early atherosclerotic lesion, that ultimately evolves into advanced atherosclerotic plaques. In this article, we will rst review lipid changes observed during APR. We also propose that inammation-associated dyslipidemia could play a central role in the pathophysiology of the metabolic syndrome and atherosclerosis. Our review is focused on the possible mechanistical advantages of inammation-associated lipoprotein changes. For academic purposes, we summarize the changes that occur in every main lipoprotein. E. Esteve et al. phosphodiesterase inhibitor, has been observed to lead to decreased plasma IL-6 concentration and a concomitant increase in HDL-C.31 Antibiotic treatment for periodontitis also raises HDL-C concentration.32 These relationships may also be observed at the genotype level. Thus, the CA16 allele of TNF-a receptor gene is associated with raised HDL-C levels in diabetic patients.33 The 174C polymorphism carriers of the IL-6 gene also show increased HDL-C levels.34 In animal studies, the infusion of cytokines led to decreased HDL-C.3540

Changes in reverse cholesterol transport

HDL is an acceptor for cholesterol efux. This process is facilitated passively by cholesteroldependent gradient diffusion of cholesterol to HDL, and actively by the interaction of pre-B-HDL and ATP binding cassette A1 (ABCA1).41 ABCA1 is a cholesterol transporter member of the ABC transporter superfamily.42 Activation of ABCA1 seems to be the rst step of the reverse cholesterol transport pathway and is therefore important in the control of plasma HDL levels. In response to lipid loading, macrophages activate a compensatory pathway for cholesterol efux to HDL mediated by the ABCA1 transporter.43 Liver X receptors (LXRs) are transcriptional regulators of cholesterol absorption, transport and elimination.44 In macrophages, LXR signalling is critical for initiating the homeostatic response to cellular lipid loading and its activation induces expression of genes involved in cholesterol efux as ABCA1, phospholipid transfer protein (PLTP) and apoE that nally transfer cholesterol excess to apoAI and apoE-binding lipoproteins.4446 In fact, synthetic LXRs reduce atherosclerosis in animal models.47 LPS and cytokines inhibit cholesterol efux from cells by reducing expression of the ABCA1 gene and increasing intracellular cholesterol concentration. IL-1 also reduces mRNA expression of PPAR and LXRa.48,49 These changes might explain the clinical observation that patients with an activated inammatory response have low circulating levels of apo A-I and HDL-C.50 Recently, it has been described that the toll-like receptors (TLRs) family protein are localized in macrophages. TLRs have the ability to recognize a wide range of microbial components and their activation lead to a rapid anti-microbial response through stimulation of pro-inammatory pathways.51 Polymorphisms in the TLR4 locus have been associated with atherosclerosis risk and enhanced

Changes in HDL lipoprotein during inammation

It is well known that HDL particles are fundamental for cholesterol reverse transport, and protect from coronary disease development.21 There are several mechanisms through which inammation and cytokines can modify the size, composition and function of HDLs. During APR a wide range of changes in HDL apolipoprotein and enzymes occurs. These changes in HDL particles caused by inammation not only reduce HDL-C levels but they also alter anti-oxidant properties of HDL and LDL protection from oxidation. It is thought that the mechanisms by which HDL-C levels decrease during inammation are due to a reduction in cholesterol uptake by cells and an increase in their catabolism.

HDL particles and inammation

Patients affected by chronic diseases like rheumatoid arthritis show decreased HDL-C levels compared with control subjects.22 An inverse correlation exists between serum HDL-C and inammation parameters (raised circulating concentration of interleukin-6 (IL-6) and soluble TNF-a receptors) in healthy subjects and patients with coronary artery disease.2329 Conversely, increased IL-10 concentration (an anti-inammatory cytokine) is associated with raised plasma HDL-C.30 Mechanistically speaking, these changes seem to be interrelated. For instance, cilostazol, a novel

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Dyslipidemia and inammation
IL, TNF, LPS

19

HDL-C
TLR
LDL-R

HDL
ApoA-I, LCAT

HDL Low-size

LDL Ox-LDL SR

LXR

Chol ABCA1

PLA2

CETP,PLTP Pre-BHDL

ApoE

PON Transferrin Ceruloplasmin

Decreased anti-oxidant properties

Figure 1 Mechanisms leading to intracellular lipid loading, impairing reverse cholesterol transport and HDL antioxidant capacity. Inammation inhibits LXR signalling impairing cholesterol efux via ABCA1, PLTP and apoE; it also overrides the suppression of LDL-R induced by a high intracellular concentration of cholesterol and induces the expression of scavenger receptors (SRs). TNF, tumor necrosis factor; IL, interleukin; LPS, lipopolysaccharide; TLR, tolllike receptor; LXR, liver X receptor; SR, scavenger receptor; LDL-R, LDL receptor; Chol, cholesterol; apoE, apolipoprotein E; ABCA1, ATP binding cassette A1; apoA-I, apolipoprotein A-I; LCAT, lecithin-cholesterol acyl transferase; sPLA2: Secretory nonpancreatic phospholipase A2 , PON, paraoxonase; CETP, cholesterol ester transfer protein; PLTP, phospholipid transfer protein; Ox-LDL, oxidized LDL.

expression of several TLRs has been detected in human atherosclerotic lesions.52,53 As recently reviewed, there is a crosstalk between LXR and TLR signalling, so that bacterial or viral stimulation of TLRs antagonize with LXR pathway and inhibit macrophage expression of ABCA1 and apoE, worsening reverse ApoAI-dependent cholesterol transport to HDL.46 Microbial activation of TLRs signalling pathways inhibit LXRdependent gene expression and reduce ABCA1 mRNA expression. IRF-3, a transcription factor of TLR, competes with LXR for a common coactivator suggesting a crosstalk at this level between cholesterol metabolism and infection. In aortic tissue, TLR-mediated inhibition of LXR activity produces cholesterol accumulation in the vessel wall, indicating a pro-atherogenic effect because accumulation of cholesterol-loaded macrophages in the arterial wall is an early atherosclerotic lesion54 (Fig. 1).

rate of HDL catabolism.56 Infusion of cytokineliberating LPS induce a decrease on hepatic and extra-hepatic apoA-I RNA messenger and apoA-I levels in rats and rabbits,40,57,58 but this effect could not be proved in other studies using different species.37,59 Direct TNF-a and IL-1 infusion in mice and monkeys reduce plasma apoA-I RNA messenger and the same happens in cultured adipocytes.38,60 Peripheral apolipoprotein J (apoJ) levels increase following endotoxin, TNF-a or IL-1 administration.61 Hepatic and extra-hepatic apo J mRNA is also increased by endotoxin and cytokines.58,61 ApoJ participates in mobilization, uptake and redistribution of lipids from damaged or lipidloaded cells and regulates vascular smooth muscle cell differentiation, an important component of atherosclerotic lesions.62,63

Changes in HDL-associated enzymes

Hepatic lipase (HL) is an enzyme synthesized in the liver and has a very important role in lipoprotein metabolism.64 It is involved in TG removal from VLDL and chylomicrons remnants facilitating the capture of these particles from circulation. It also plays a role in the conversion from VLDL to LDL and hydrolyzes HDL TGs. This results in the formation of

Changes in HDL-associated apolipoproteins

ApoA-I is the principal structural apolipoprotein of HDL and reverse cholesterol transport requires apoA-I for cholesterol removal from cells.55 In fact, HDL size is one of the major determinants of the

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20 small pre-B HDL particles, with an important role in the cholesterol removal from cells.65 In mice, rats and humans a decrease in plasma HL activity during APR has been demonstrated.6670 Endotoxin and IL1 produce a marked decrease in HL mRNA levels in vivo (by 75% in mice) and in vitro (hepatic cell lines).71 A decrease in HL during APR could contribute to the increase in serum TG levels by (a) decreasing the removal of TGs from VLDL and chylomicrons and (b) the reduction in reverse cholesterol transport, given the increase in TG-rich HDL.72 Inammation also induces a reduction of lecithincholesterol acyl transferase (LCAT) activity both in vivo and in hepatocytes in vitro.35,7375 LCAT is a fundamental enzyme in cholesterol re-esterication, establishing and maintaining a free cholesterol gradient which allows a cholesterol movement from cells to HDL particles resulting in larger HDL. During APR and inammation, a reduction in mRNA expression and in the activity of cholesterol ester transfer protein (CETP) and PLTP have been observed, contributing to changes in HDL metabolism and function.7679 CETP exchanges cholesterol esters from HDL to TGs in TG-rich lipoproteins. If this transfer decreases, a reduction of hepatic clearance of cholesterol will ensue. PTLP mediates a transfer of phospholipids and cholesterol between TG-rich lipoproteins and HDL. A reduction of PLTP activity could decrease cell cholesterol removal given the resulting reduction of cholesterol exchange into TG-rich lipoproteins and the reduction in HDL levels.80 All changes in reverse cholesterol transport enzymes lead to lower HDL levels, decrease in the size of these lipoproteins and changes in their composition, resulting in a decrease of cholesterol esters and an increase in free cholesterol and TG HDL levels.73,75,81 These small HDL particles have faster catabolism and elimination from circulation.56,82 On the other hand, acute-phase HDL have less paraoxonase (PON) levels.83 This protein protects LDL from oxidative stress.84 Depletion of PON results in the loss of anti-oxidant function of HDL.85,86 During inammation or infusion of endotoxin, TNF-a and IL-1, PON activity decreases in both human and rodents. In fact, LDL oxidation has been observed to follow the time course of inammation-induced decrease in PON activity.83,87 Secretory non-pancreatic phospholipase A2 (sPLA2) is another acute-phase protein that is increased during infection and inammation and is associated with HDL particles.8890 Cytokines (IL6) stimulate the hepatic production and secretion of sPLA2.89 sPLA2 levels are predictive of coronary E. Esteve et al. artery disease and accelerates the development of atherosclerosis.91,92 It hydrolyzes HDL phospholipids and reduces HDL size without generating preBHDL, which induces their catabolism.93 Overexpression of sPLA2 in transgenic mice decrease the concentration of HDL cholesterol, apoA-I and phospholipids and increase HDL TGs and proteins.93,94

Changes in other HDL-associated proteins

In APR, there are changes in some other proteins that contribute to the changes in reverse cholesterol transport and to decreased anti-oxidant activity of HDL particles. Transferrin is a metal-binding protein associated with HDL which shows anti-atherogenic functions.95 During APR, hepatic synthesis and HDL binding of transferrin decreases, resulting in a decreased protecting ability of HDL against LDL oxidation.79 Ceruloplasmin is an APR protein associated with HDL, which increases during inammation. Its role during inammation is not clear because in some studies ceruloplasmin-associated HDL is thought to have anti-oxidant properties,96 while in others it results in enhanced LDL oxidation.97,98 Another HDL protein that increases during inammation is serum amyloid A (SAA).99,100 SAA-rich HDL binds to macrophages rather than hepatocytes in vitro suggesting that HDL-C may be preferentially directed to macrophages.101 This means that SAArich HDL particles are less available to be metabolized by the liver. Nevertheless, in human apoA-I transgenic mice overexpression of acute-phase SAA did not have any effect on HDL-C.102 However, one property of SAA might be to activate sPLA2, as observed in in vitro studies, but this hypothesis was not conrmed in animal studies.93103

Changes in phospholipids
Phospholipids, as components of lipoprotein surfaces, are the most important determinants of LPS lipoprotein binding. The ability of different lipoprotein classes to neutralize LPS depends on their phospholipid content but not on their cholesterol or TG composition.104 Phospholipidcholesterol ratio is the strongest predictor of LPS binding activity.105 Other predictors of LPS binding are the content of apoE, apoB and the absolute value of LDL-phospholipids.105 LPS-binding protein (LBP) is able to transfer LPS into phospholipid vesicles and into articial phospholipid-rich particles or emulsions resulting in an increased protection against adverse effects of LPS.106109

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Dyslipidemia and inammation In normal human plasma, HDL contains the majority of circulating phospholipids and is the principal LPS-binding particle.110,111 During infection, HDL-total phospholipids decrease, resulting in a decreased HDL-LPS binding activity.32,105 Simultaneously, VLDL and LDL-phospholipids rise, increasing in parallel their ability to bind LPS, becoming the main LPS binding lipoproteins during severe infection.105 These changes in VLDL and LDL phospholipid levels could suggest a compensatory mechanism to protect the host from LPS, and might mechanistically explain why TG levels increase during APR. 21 correlate with postprandial TGs.127130 On the other hand, the opposite is observed with the anti-inammatory cytokines, such as IL-10. Lower TG, LDL-C and TC and higher plasma HDL-C are shown when IL-10 levels increase.30 The therapy with brates and statines not only reduces TGs, but also cytokines (IL-6) and acutephase proteins (CRP), suggesting a possible link between both pathways.125,126,131 As exposed above, cilostazol, which has also been shown to have benecial effects on dyslipidemia, by reducing TGs and raising HDL-C, leads also to reduced IL-6 levels.31 At the genetic level, similar relationships are found. TNFRSF1B polymorphism of the TNF receptor gene is associated with susceptibility to familial combined hyperlipidemia in healthy controls and in patients with ischemic heart disease subjects.132134 The NcoI polymorphisms of the TNF-a and TNF-b genes also seem to be linked with increased basal and postprandial TGs in some but not all studies.135137 In the same direction, the carriers of the 174G allele of the IL-6 gene show increased TG, VLDL-Tg and decreased HDL-C levels, in parallel to increased transcription rate of this cytokine.34

Changes in VLDL lipoprotein and TGs during inammation

Elevation of TG levels is considered as an independent cardiovascular risk factor, especially in the diabetic population.112114 Nevertheless, it is difcult to establish an independent association between TGs and cardiovascular risk due to their close relation with HDL-C levels.115

TGs and inammation

In subjects with frequent infections and/or chronic infection, hypertriglyceridemia is well described. It occurs in diseases such as AIDS, cystic brosis or systemic lupus erythematosus (SLE).116,117 In AIDS, plasma TG, VLDL-TG, VLDL-C and apoB correlate with IFN-a levels.118,119 In patients with SLE, a positive correlation is observed among peripheral TNF-a levels and TG, VLDL-TG or VLDL-C.117 In healthy people, TNF-a and the soluble fraction of TNF-a receptor (sTNFR) 2 correlate positively with plasma TGs and negatively with HDL-C.27,29 In hypertension and in subjects affected from coronary heart disease, TNF-a is also linked to TG levels, and correlate negatively with HDLC.25,120,121 In ischemic chronic heart failure (CHF) an association exists between parameters of inammation and lipids, while in others causes of CHF this is not usually observed.122 IL-6 is also linked to dyslipidemia, metabolic syndrome and atherosclerosis.123,124 IL-6 levels are associated with higher TGs and lower HDL-C levels in healthy subjects, in patients with dyslipidemia, in type 2 diabetic patients and also in subjects with increased prevalence of cardiovascular disease.23,26,34,125,126 Interestingly, while increased postprandial TGs and TG-rich lipoproteins have been associated with increased cardiovascular risk, IL-6 and also TNF-a levels have been described to

Pathophysiology of TG disturbances
Hypertriglyceridemia-associated inammation has been attributed to both decreased lipoprotein clearance and increased lipoprotein production. It could reect a compensatory mechanism for the decrease in HDL-C and phospholipids levels (Fig. 2). Increased lipoprotein production The increase in hepatic TG-rich particles production is secondary to an increase in re-esterication of plasma fatty acid arising from both enhanced lipolysis and increased fatty acid synthesis in the liver.37,138141 Increased lipolysis results in a greater free fatty acid ux to the liver, thereby promoting lipoprotein VLDL secretion.142 The increase in lipolysis which occurs in inammation is mediated by both hormone- and non-hormone-sensitive lipase.143 Several cytokines can also stimulate the synthesis of cortisol and catecholamines that lead to increased lipolysis.144 Infusion of LPS and different cytokines such as TNF-a, IL-1, IL-2, IFN-a and IL-6 increase plasma TGs by stimulating secretion of hepatic-rich TG VLDL particles,36,37,145148 but, in some studies, continuous cytokine infusion of supraphysiological doses have been described to reduce plasma

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22
Increased production
TNF- IL-1 IL-6

E. Esteve et al.

FAA

Adipocyte

TNF- IL-1 IL-6

ApoE TG-rich VLDL

CETP

HDL

LPL

IDL

Decreased clearance

LDL

Figure 2 Mechanisms of hypertriglyceridemia production associated to inammation. The increase in hepatic TG-rich particles production is secondary to an increase in re-esterication of plasma fatty acid arising from both enhanced lipolysis and increased fatty acid synthesis in the liver. Inammation can also inhibit TG clearance by reducing LPL activity and reducing VLDL-associated apoE levels (impairing the cellular uptake of TG-rich particles). TNF, tumor necrosis factor; IL, interleukin; apoE, apolipoprotein E, cholesterol ester transfer protein; LPL, lipoprotein lipase; TG, triglyceride; FAAs, free fatty acids.

TG.149,150 In vitro, TNF-a and IL-1 also stimulate TG synthesis in hepatic cell lines.151 These changes are mediated by induction of lipolysis or increased de novo fatty acid synthesis.138,152159 While TNF-a induces lipolysis and de novo fatty acid synthesis (in part by reducing adiponectin synthesis and inhibiting insulin signalling), IL-1 stimulates mainly de novo fatty acid synthesis.160,161 Diet can modify cytokine effect on lipid synthesis. In chow-fed animals, TNF-a stimulate both lipolysis and hepatic fatty acid synthesis while in sucrose-fed animals TNF-a induce only hepatic fatty acid synthesis but not lipolysis.153

Decreased lipoprotein clearance Inammation can reduce the clearance of TG-rich particles, although this pathway seems to be quantitatively less important. High doses of LPS can inhibit TG clearance by reducing lipoprotein lipase (LPL) activity.162163 In cultured adipocytes or endothelial cells, and in animals, TNF-a, IL-1, IL6 and IFN-a reduce LPL activity.4,154,164171 In humans, administration of IFN-a, IFN-g and IL-6 leads to reduced LPL activity and increased TG levels.172,173 Cytokine action on LPL activity does not participate in acute hypertriglyceridemia but in the delayed elevation of TG of chronic inammation.174176

The reduction observed in VLDL-associated apoE levels could be another mechanism through which TG clearance can be delayed.177 ApoE is essential for the cellular uptake of TG-rich particles. TNF-a and IL-1 leads to reduced hepatic and extra-hepatic apoE RNA messenger, decreasing apoE secretion in animals and cultured cells.38,39,58,178,179 During inammation, the lipid changes that are observed are not only quantitative but also qualitative, with changes in the composition of lipoproteins. Thus, the proportion of TGs, phospholipids and cholesterol is increased in VLDL, IDL and LDL lipoproteins while the proportion of cholesterol and TGs decrease in HDL particles.40 As noted above, the increase in VLDL-phospholipids enhances LPS binding and could behave as a compensatory mechanism resulting from the decrease in HDL phospholipids.15,105,180

Changes in LDL lipoprotein and cholesterol during inammation

Most of the LDL particles are derived from the intravascular catabolism of VLDL. Catabolism of LDL occurs in both peripheral cells and the liver and is facilitated by both LDL-receptor- (LDL-R-) mediated and non-receptor-mediated pathways.

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Dyslipidemia and inammation Clinical and epidemiological studies have shown LDL-C as one of the most important cardiovascular risk factors. 23

Changes in LDL-C clearance during infection

LDL-R activity is under tight metabolic control by intracellular cholesterol concentration through feedback system.189 Inammation causes dysregulation of LDL-R expression, and TNF-a and IL-1 override the suppression of LDL-R induced by a high intracellular concentration of cholesterol.190,191 Inammation also induces the expression of scavenger receptors (SRs) and foam cells generation, by increasing SR gene promoter activity.48 SR activity is not suppressed by rising intracellular cholesterol concentration because they show no regulated cholesterol uptake. Cholesterol accumulation by LDL-R dysregulation or SR pathways, in addition to decreasing ABCA-1-dependent cholesterol efux, leads to foam cell formation, the rst phase in atherosclerotic plaque generation. These mechanisms of cholesterol cell accumulation could also explain why human plasma LDL-C decreases during the APR. The intensity and duration of the stimulated production of cytokines might contribute to explain the opposite and changing actions of TNF-a on cholesterol metabolism. Chronic activation of the inammatory cascade may activate pathways of cholesterol metabolism such increased LDL-R expression leading to increased lipoprotein clearance, conversion of newly synthesized into bile acids or enhanced esterication and storage of cholesterol.192

LDL-C and inammation

The effect of cytokines on cholesterol metabolism is species specic, being different in primates and other species, including man. In rodents, LPS and cytokines lead to an increase in serum cholesterol (total and LDL-C) and to an increase in cholesterol synthesis whereas in primates these same factors lower cholesterol levels.36,7274,181182 Plasma LDL-C levels decreases during sepsis in humans and this decrease is signicantly associated with increased mortality rate.183,184 In conditions of chronic inammation such as AIDS and cystic brosis, decreases in total and LDL-C are usually found, but these ndings are controversial.68,70 In fact, positive associations between circulating TNFa and LDL-C levels, and between IFN-a and LDL-C have been described in healthy subjects and in VIH patients, respectively.27,119 The circulating concentration of the sTNFRs 1 and 2 have been also associated with increased LDL-C levels in healthy subjects and in patients with coronary artery disease.25,29 Interestingly, an increased transcription rate attributed to cytokine gene variants leads to differences in plasma lipid concentrations. In this sense, a TNF-b gene promoter NcoI polymorphism was found to be associated with increased plasma LDL-C levels in one study.185 On the contrary, serum LDL-C gradually decreases over strata representing higher anti-inammatory IL-10 production capacity.30 A regulatory effect of diet in these changes has been observed during low-fat diet, where subjects with higher CRP levels showed less LDL-C reduction than people with lower CRP levels. This nding suggests a decreased response to diet with increased inammation.186 The increase in cholesterol that occurs during APR may be the result of increased synthesis and/or decreased clearance by LDL-R. LPS, TNF-a and IL-1 administration in rodents produced an increase in hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase mRNA levels, the rate-limiting enzyme in hepatic cholesterol synthesis and secretion. In contrast, these agents caused minimal effects on hepatic LDL-R mRNA expression.36,38,72 In primates, TNF-a infusion led to decreased serum cholesterol whereas IL-1 had no effects.4,73 In human hepatic cell lines, administration of TNFa and IL-6 decreased apoB secretion while IL-1 inhibited cholesterol synthesis.187,188

LDL size and oxidative modications during inammation

In addition to the changes in LDL-C levels observed during inammation, a change in LDL size and increased susceptibility to the oxidation of these particles are also observed. TNF-a levels in humans correlate negatively with peak particle size.27,193 Higher TNF-a levels are associated with lower LDL size and LPS administration in primates decrease LDL-C levels but increase the smaller and denser LDL. Smaller LDL particles show increased atherogenicity given their decreased afnity for LDL-Rs, higher capacity for oxidation and higher ability to cross over the intima artery wall and its increased uptake by foam cells.194,195 Enhanced LDL oxidation has been documented during infection and inammation.196 Oxidized LDL are more atherogenic, as they increase synthesis and secretion of adhesion molecules, enhance smooth muscle proliferation and increase cytotoxity to endothelial cells.197 Oxidized LDL particles induce foam cell formation by increasing oxidized

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24 LDL afnity for the SR. Part of the increase in LDL oxidation is due to decreasing HDL protective action observed during the APR. The changes observed in HDL during inammation, as the decrease of transferrin and PON activity and the increase in ceruloplasmin levels, can contribute to the increase in LDL susceptibility to oxidation.83,87,95,198 E. Esteve et al. tion is ensured by the large amount of cholesterol carried by the lipoprotein. In contrast to other cholesterol-rich lipoproteins, Lp(a) concentration is not substantially inuenced by changes in dietary habits. Therefore, it is conceivable that, given the different dietary habits of primates several million years ago, and the much lower plasma levels of TC and LDL-C, the amount of cholesterol carried by Lp(a) might have represented an important source of substrates for cell regeneration and growth.

Lipoprotein(a), inammation and tissue repair

It has been hypothesized that Lp(a) could offered an evolutionary advantage to humans by promoting or accelerating the healing of wounds and the repair of tissue injuries and vascular lesions.199 In fact, Lp(a) behaves as an acute-phase reactant. The sequence of the apo(a) gene contains several IL-6-responsive elements that enhance transcription of the gene.200 IL-6 generates a marked, dosedependent enhancement of apo(a) mRNA synthesis that leads to the accumulation of Lp(a) particles in hepatocyte culture,201 and signicant rises in plasma Lp(a) are observed after inducing different forms of APR in vivo.202 Due to the additional presence of apo(a), Lp(a) can be recognized by a broad variety of receptors at the surface of endothelial cells, macrophages, broblasts and platelets.203,204 Defensin, a peptide released from activated or senescent neutrophils, enhances the binding of Lp(a) to endothelial cells by approximately four-fold and to smooth muscle cells by sixfold.205 The large amount of cholesterol carried by the lipoprotein can easily be extracted and used at the site of its accumulation. Lippi and Guidi199 reviewed that Lp(a) could have been an essential component for tissue repair, whose primary functions might have been the delivery of large amount of cholesterol to peripheral cells and the promotion of regeneration following events such as injuries or inammatory processes. Their hypothesis was as follows: As a vascular injury occurs, the APR, concomitantly induced by the cellular release of several mediators, including IL-6, stimulates the hepatic synthesis of newly formed apo(a) molecules. Shortly afterwards, Lp(a) accumulates at the site of the vascular injury as it binds to cellular receptors at the surface of residual vascular cells, macrophages and platelets. The large amount of apo(a) bound to the brin surface, platelets and endothelial cells, inhibits the lysis of the clot. At the same time, the growth-factor-like properties of Lp(a) promote vascular repair, and cell regenera-

Conclusions
Lipoproteins can decrease the toxicity of a variety of harmful biological and chemical agents. Lipoproteins are directly involved in the host response to infection and tissue destruction. During acute illness, delivery of cholesterol to the liver for excretion is altered to allow cholesterol to remain in the tissues where it is needed for repair and regeneration of damaged membranes. In fact, lipoproteins have been found to be potent inhibitors of the infectivity of different viruses and to have powerful anti-parasitic activity. In animal models, it is rmly established that LDL and VLDL are critical in the survival of infection with Gramnegative bacteria.206 Circulating cholesterol-rich and TG-rich lipoproteins have the capacity to bind and detoxify bacterial lipopolysaccharide (LPS). Daily activities in healthy people, such as brushing teeth and defecating, often introduce LPSs into the circulation. LBP circulates in association with apo-B containing lipoproteins. LPB is required to induce a rapid inammatory response, which is essential for the resistance to bacteria. High concentrations of LBP inhibit LPS effects and prevent mortality induced by endotoxemia.207 Lipoproteins also carry the LPS binding receptor, CD14, with important functions in triggering host defences. The uptake of LPS into LDL, considered benecial during acute infection, is thought to be potentially harmful during chronic inammation. Transport of LDLLPS complexes into the artery wall might initiate an inammatory response and provoke an atherosclerotic reaction. This apparent paradox would explain why high cholesterol levels are proatherogenic in the long term. Subjects who survivei.e. the elderly population with lower cholesterol concentrationswould be more vulnerable to external noxa (infectious agents, poor recovery from trauma) if serum cholesterol concentrations are below a hypothetical security limit.

ARTICLE IN PRESS
Dyslipidemia and inammation In fact, low cholesterol concentrations have been associated with violence-related mortality and death from injuries.208 Low cholesterol also predicts an increased risk of death from infection, mainly from the respiratory and digestive tracts.209 Subjects with hypocholesterolemia display a poor defence in situations of tissue-stress related to external phenomena.210 It cannot be excluded that low cholesterol is also a marker for decreased antioxidant capacity (Vitamin E circulates in lipoprotein) or deciency in other essential fatty acids. When the compensatory response (inammation) is not able to repair injury, it turns into a harmful reaction, and lipid changes will become chronic, either for repeated or overwhelming stimulus, and will enhance the formation of atherosclerotic lesions. The inammatory cascade will induce a decrease in HDL-C, impairing reverse cholesterol transport, changing apolipoproteins, enzymes, anti-oxidant capacity and ABCA1-dependent efux. This could be due to an evolution-conserved mechanism aimed at accumulating cholesterol in cells during infection. This decrease in HDL-C and phospholipids could stimulate compensatory changes, as synthesis and accumulation of phospholipid-rich VLDL binds LPS and other toxic substances, resulting in hypertriglyceridemia. Thus, these classical lipid changes associated with the metabolic syndrome (increased TGs and decreased HDL-C) may be envisioned as a highly conserved evolutionary response aimed at tissue repair. Under this assumption, the problem is not the response but the persistence of the stimulus. 25
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