Circulation Research. 2007;100:299-301
doi: 10.1161/01.RES.0000259393.89870.58
(Circulation Research. 2007;100:299.)
© 2007 American Heart Association, Inc.
Fat Fuels the Flame
Triglyceride-Rich Lipoproteins and Arterial Inflammation
Peter Libby
From the Division of Cardiovascular Medicine, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Peter Libby, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
See related article, pages 381390
Key Words: very low density lipoprotein endothelium apolipoprotein CIII atherosclerosis coronary risk factors
 |
Introduction
|
|---|
Recent reviews duly recite the prevailing concept of the mechanisms
of atherogenesis.
15 According to this model, a surfeit
of low-density lipoproteins (LDL) favors accumulation and retention
of these particles in the arterial intima. There, LDL undergoes
oxidative modification. Lipid mediators derived from this oxidized
LDL stoke the inflammation now widely deemed a critical culprit
in the formation and complication of atheroma.
6
 |
Does the Prevailing Model Explain Atherogenesis?
|
|---|
This oft repeated schema rests on a firm experimental foundation.
Clinical and human pathological observations corroborate this
view. Yet, the "oxidized LDL" hypothesis may not explain all
aspects of atherogenesis. Most laboratory experiments with oxidized
LDL use mixtures of products of incubation of LDL with transition
metals. The Fenton chemistry used to generate oxidized LDL in
the laboratory may have little to do with the oxidative processes
at work in the atherosclerotic arterial wall. Biochemical studies
have however begun to identify the structures of components
oxidized LDL that do elicit proinflammatory effect on cells
involved in atherogenesis.
3,4 The lack of clinical benefit of
antioxidant vitamin supplements does not alone vitiate a pathogenic
role for oxidized LDL.
7,8 Antioxidant vitamins may well not
distribute to the proper compartments or may be chemically inappropriate
agents for the oxidation chemistry that pertains to lipoproteins
entwined with the intimal extracellular matrix during atherogenesis.
The clinical trials of antioxidant vitamins may have enrolled
patients at a stage of their disease too advanced to show a
benefit of the antioxidant strategy.
LDL lowering does consistently confer clinical benefit, even in trials in which antioxidants have failed to do so. Yet the most aggressive LDL-lowering regimens still do not prevent the majority of events.9 For these reasons, we need to seek pathways beyond LDL that drive atherogenesis and its associated heightened inflammation.
 |
Lipid Triggers for Atherogenesis Beyond LDL
|
|---|
Manipulation of high-density lipoprotein (HDL) furnishes one
attractive strategy. Numerous observational studies support
strongly the inverse association of HDL and cardiovascular events.
Strong experimental and human genetic studies have revealed
molecular pathways by which HDL may protect against atherosclerosis
by effecting reverse cholesterol transport or by antiinflammatory
actions. Diet, physical activity, and some classes of pharmacological
agents can raise HDL levels, but we still lack clinical evidence
that therapeutic elevation of HDL confers clinical benefit.
The recent finding reported in the lay press of excess mortality
with one cholesteryl ester transfer protein inhibitor that handsomely
boosted HDL level could relate to an idiosyncratic effect of
that particular molecule or to inefficacy of this approach to
HDL elevation. Conclusions in this regard must await at least
the analysis and publication of the clinical end point and imaging
trials with this agent.
Levels of HDL usually vary inversely with triglyceride concentration. Epidemiologists still fret over whether triglycerides actually comprise a risk factor for cardiovascular events independent of HDL or of glycemic control in diabetic individuals. Triglyceride levels depend exquisitely on diet and vary from hour to hour, challenging such analysis in large populations, and rendering HDL the more reliably measured of the twain. Partly for this reason, the notion of postprandial lipemia as an atherogenic risk factor, championed by Zilversmit, remains incompletely explored.10 Turning the usual notion on its head, could the traditional dependent variable in such analyses (triglyceride levels) become the independent variable? Could triglyceride-rich lipoproteins directly promote atherogenesis and trigger inflammation? Should triglyceride-rich lipoproteins become a target for intervention?
 |
Proinflammatory Mechanisms of Triglyceride-Rich Lipoproteins?
|
|---|
Dwarfed by the voluminous data regarding proinflammatory effects
of LDL and its derivatives, we possess scant information about
triglycerides or triglyceride-rich lipoproteins as instigators
of inflammation and other atherogenic functions of cells found
in plaques. In 1999, Dichtl and colleagues reported that the
triglyceride-rich lipoprotein very low-density lipoprotein (VLDL)
activates the pivotal transcriptional regulator of inflammation
nuclear factor-kappa B (NF-

B).
11 As lipoproteins can bind bacterial
lipopolysaccharides, ubiquitous laboratory contaminants that
can activate inflammatory signaling in vascular cells and leukocytes
in minute concentrations, such results bear careful scrutiny
and replication. In this issue of
Circulation Research Ting
et al provide further independent data that support a role for
triglyceride-rich lipoproteins in inflammatory activation of
vascular cells in vitro.
12 They found that triglyceride-rich
lipoproteins at postprandial concentrations do not alone elicit
an inflammatory response in human aortic endothelial cells.
Treatment of the endothelial cells with the triglyceride-rich
lipoproteins did substantially raise the expression of leukocyte
adhesion molecules and monocyte adherence in response to the
proinflammatory cytokine tumor necrosis factor-

(TNF-

). Lipopolysaccharide
levels measured in the lipoprotein preparations appeared low.
The mechanism of this effect appeared to depend on LDL-receptor
related proteins (LRP) and downstream activation of p38 MAP
kinase and NF-

B (
Figure). The disparity between the Dichtl study
that showed direct effects of VLDL on NF-

B activation and the
Ting study that demonstrated a potentiation of cytokines but
no direct effect of triglyceride-rich lipoproteins alone on
inflammatory functions of endothelial cells, will require further
study. The specter of endotoxin contamination demands eternal
vigilance in such quests. Interestingly, Stollenwerk et al showed
that in human monocyte-derived macrophages VLDL potentiated
lipopolysaccharide-induced TNF-

expression but by itself did
not do so.
13 Another pro-inflammatory mechanism of triglyceride-rich
lipoproteins could depend on their content of apolipoprotein
CIII. Our recent work has shown that apolipoprotein CIII or
VLDL that bear this apolipoprotein can increase monocytoid cell
adhesion to endothelial cells in a vascular cell adhesion molecule-1dependent
manner.
14,15 Apolipoprotein CIII appears to activate NF-

B through
a pertussis-sensitive G protein-protein kinase Cdependent
pathway.
16 Thus, triglyceride-rich lipoproteins can fan the
flame of inflammation during atherogenesis in several ways (
Figure).
 |
Putting Proinflammatory Mechanisms of Triglyceride-Rich Lipoproteins in Clinical Context
|
|---|
The risk factor profile of the typical patient with atherosclerosis
is shifting at the advent of the 21st century. Our armementarium
includes effective and clinically proven interventions to address
high levels of LDL, the cardiovascular scourge of the latter
half of the 20th century. We now face a burden of obesity and
diabetes, and the attendant dyslipidemia noteworthy for elevated
triglyceride-rich lipoproteins and low HDL rather than excessive
LDL levels. Thus, the pressing current clinical cardiovascular
challenges include mastery of triglyceride-rich lipoproteins.
The emerging data regarding pathways that link features of dyslipidemia
to inflammation and atherogenesis provide new insight into the
mechanisms that underlie a burgeoning epidemic of heightened
atherosclerotic risk because of dyslipidemia.
 |
Acknowledgments
|
|---|
Sources of Funding
This work is supported by the Donald W. Reynolds Foundation and the National Heart, Lung, and Blood Institute.
Disclosures
None.
 |
Footnotes
|
|---|
The opinions expressed in this editorial are not necessarily
those of the editors or of the American Heart Association
 |
References
|
|---|
- Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 16851695.[Free Full Text]
- Glass CK, Witztum JL. Atherosclerosis. the road ahead. Cell. 2001; 104: 503516.[CrossRef][Medline]
[Order article via Infotrieve]
- Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Fonarow GC, Vahabzadeh K, Hama S, Hough G, Kamranpour N, Berliner JA, Lusis AJ, Fogelman AM. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res. 2004; 45: 9931007.[Abstract/Free Full Text]
- Berliner JA, Watson AD. A role for oxidized phospholipids in atherosclerosis. N Engl J Med. 2005; 353: 911.[Free Full Text]
- Libby P, Ridker PM. Inflammation and atherothrombosis: from population biology and bench research to clinical practice. J Am Coll Cardiol. 2006; 48: A33A46.[Abstract/Free Full Text]
- Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6: 508519.[CrossRef][Medline]
[Order article via Infotrieve]
- Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL. Antioxidant vitamin supplements and cardiovascular disease. Circulation. 2004; 110: 637641.[Free Full Text]
- Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J, Jr. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354: 15671577.[Abstract/Free Full Text]
- Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005; 46: 12251228.[Abstract/Free Full Text]
- Zilversmit DB. Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins. Clin Chem. 1995; 41: 153158.[Abstract/Free Full Text]
- Dichtl W, Nilsson L, Goncalves I, Ares MP, Banfi C, Calara F, Hamsten A, Eriksson P, Nilsson J. Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells. Circ Res. 1999; 84: 10851094.[Abstract/Free Full Text]
- Ting HJ, Stice JP, Schaff UY, Hui DY, Rutledge JC, Knowlton AA, Passerini AG, Simon SI. Triglyceride-rich lipoproteins prime aortic endothelium for inflammatory responses to TNF-
. Circ Res. 2007; 100: 381390.[Abstract/Free Full Text] - Stollenwerk MM, Schiopu A, Fredrikson GN, Dichtl W, Nilsson J, Ares MP. Very low density lipoprotein potentiates tumor necrosis factor-alpha expression in macrophages. Atherosclerosis. 2005; 179: 247254.[CrossRef][Medline]
[Order article via Infotrieve]
- Kawakami A, Aikawa M, Libby P, Alcaide P, Luscinskas FW, Sacks FM. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation. 2006; 113: 691700.[Abstract/Free Full Text]
- Kawakami A, Aikawa M, Alcaide P, Luscinskas FW, Libby P, Sacks FM. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation. 2006; 114: 681687.[Abstract/Free Full Text]
- Kawakami A, Aikawa M, Nitta N, Yoshida M, Libby P, Sacks FM. ApolipoproteinCIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G-protein- and protein kinase Ca-mediated nuclear factor-kB activation. Arterioscler Thromb Vasc Biol. 2007; 27: 219225.[Abstract/Free Full Text]
Related Article:
-
Triglyceride-Rich Lipoproteins Prime Aortic Endothelium for an Enhanced Inflammatory Response to Tumor Necrosis Factor-
- Harold J. Ting, James P. Stice, Ulrich Y. Schaff, David Y. Hui, John C. Rutledge, Anne A. Knowlton, Anthony G. Passerini, and Scott I. Simon
Circ. Res. 2007 100: 381-390.
[Abstract]
[Full Text]
[PDF]