6 Journal of Atherosclerosis and Thrombosis  Vol.16, No.

Review

Apolipoprotein CⅢ Links Dyslipidemia with Atherosclerosis

Akio Kawakami 1, 2 and Masayuki Yoshida 2

1
Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan
2
Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Tokyo, Japan

Plasma levels of lipoproteins that contain apolipoprotein (apo) CⅢ predict coronary heart disease
(CHD), and associate with contributors to metabolic syndrome such as type 2 diabetes and hyper-
triglyceridemia. ApoCⅢ causes hypertriglyceridemia by inhibiting the catabolism and the clearance
of TG-rich lipoproteins (TLRs), and the association of apoCⅢ with CHD has been commonly
attributed to these properties; however, it has been untested whether apoCⅢ itself or in association
with lipoproteins directly affects atherogenic mechanisms in vascular cells. This review describes the
proatherogenic effect of apoCⅢ-containing lipoproteins. In brief, apoCⅢ-rich VLDL (VLDL CⅢ＋)
increased the adhesion of human monocytes to vascular endothelial cells (ECs). ApoCⅢ alone also
increased monocyte adhesion to vascular ECs. Interestingly, apoCⅢ-rich HDL did not reduce the
adhesion of monocytes to vascular ECs, whereas HDL without apoCⅢ decreased their adhesion, sug-
gesting that apoCⅢ in HDL counteracts the anti-inflammatory property of HDL. ApoCⅢ alone as
well as VLDL CⅢ＋ also activated vascular ECs through the activation of NF-κB, and induced the
recruitment of monocytes to vascular ECs. Moreover, apoCⅢ induced insulin resistance in vascular
ECs and caused endothelial dysfunction. These findings indicate that apoCⅢ in TLRs not only
modulates their metabolism, but also may directly contribute to the development of atherosclerosis
by activating the proinflammatory signal transduction of vascular cells. Here, we propose a novel role
for apoCⅢ that links dyslipidemia with atherosclerosis.

J Atheroscler Thromb, 2009; 16:6-11.

Key words; Inflammation, Monocyte-endothelial interaction, Hypertriglyceridemia, Metabolic syndrome

gene via the promoter IRE (insulin-response element) 4).

Introduction
The human apoCⅢ gene is expressed in the liver
and intestine, comprising a gene cluster together with
apoAⅠ and apoAⅣ genes on the long arm of chromo-
some 11 1-3). ApoCⅢ is synthesized by the liver, and
by the intestine to a lesser extent, as a 99-amino acid
peptide. After removing the 20-amino acid peptide in
the endoplasmic reticulum, a mature apoCⅢ protein
is composed of 79 amino acids with a molecular mass
of 8.8 kDa 1, 2).
Several pathways regulate apoCⅢ gene expres-
sion. Insulin reduces the transcription of the apoCⅢ
Address for correspondence: Akio Kawakami, Geriatrics and
Vascular Medicine, Tokyo Medical and Dental University
1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
E-mail: kawakami.vasc@tmd.ac.jp
Received: July 17, 2008
Accepted for publication: September 9, 2008
The expression and secretion of apoCⅢ increase in
insulin-resistant states 5). Indeed, plasma apoCⅢ is
elevated in metabolic syndrome and type 2 diabetes
and correlates with BMI and HOMA-IR 6, 7). Tran-
scription of the apoCⅢ gene is also down-regulated by
PPARs, especially PPARα8). In contrast, the activation
of NF-κB leads to up-regulation of the apoCⅢ gene
expression 3).
ApoCⅢ resides on the broad distribution of
apoB lipoproteins such as chylomicron, VLDL, IDL,
and LDL. It also resides on particles slightly larger
than HDL. In the fasting state, apoCⅢ is mainly asso-
ciated with HDL, whereas in the fed state, apoCⅢ
preferentially redistributes to chylomicron and VLDL
particles. In normotriglyceridemic patients, about half
to two-thirds of VLDL and IDL particles have apoCⅢ.
In contrast, apoCⅢ is contained in only about 10% of
LDL particles 2).
 ApoCⅢ Induces Atherosclerosis
ApoCⅢ Causes Hypertriglyceridemia
ApoB lipoproteins with apoCⅢ are rich in both
triglyceride (TG) and cholesterol ester, and are selec-
tively elevated in patients with hypertriglyceridemia.
Plasma total apoCⅢ concentration and apoCⅢ con-
centrations in apoB lipoproteins causally correlate with
plasma TG concentrations 9). ApoCⅢ causes hyper-
triglyceridemia through several mechanisms. ApoCⅢ
inhibits the catabolism and clearance of TG-rich lipo-
proteins (TRLs). Previous studies have demonstrated
that apoCⅢ on chylomicrons and VLDL inhibits their
uptake by hepatocytes in vitro and in vivo 10, 11). ApoCⅢ
inhibits the binding of apoB lipoproteins to hepatic
apoB/E receptor 12). This inhibitory action of apoCⅢ
was due to a masking of the receptor domain of apoB
or apoE 13). ApoCⅢ also inhibits LPL activity 14) and is
one of the most specific inhibitors of LPL in hyper-
triglyceridemic patients. Subjects lacking apoCⅢ have
low TRL levels 15); sera from these subjects are able to
activate human milk LPL, whereas normal sera effec-
tively inhibit LPL activity. These findings suggest that
apoCⅢ contributes to the development of hypertri-
glyceridemia by inhibiting the LPL-mediated lipolysis
of TRLs. More recently, apoCⅢ has been shown to
stimulate VLDL synthesis in cultured hepatocytes 3).
Several kinetic studies using an isotope tracer
showed that elevated apoCⅢ concentrations associated
with increased VLDL secretion as well as decreased
VLDL catabolism in subjects with metabolic syndrome
and hypertriglyceridemia 16). Studies using transgenic
and knockout mouse models support the apoCⅢ
effect on the metabolism of TRLs. Overexpression of
human apoCⅢ in wild-type mice or in LDL receptor
knockout mice not only induced hypertriglyceride-
mia, but also enhanced the development of atheroscle-
rosis 17, 18). In these models, elevated apoCⅢ concentra-
tions associated with the increased hepatic VLDL pro-
duction rate and decreased catabolic rate of VLDL and
their remnants. In contrast, apoCⅢ knockout mice
showed the rapid catabolism of TRLs and hypotriglyc-
eridemia 19).
ApoCⅢ Predicts CHD Risk
As apoCⅢ is elevated in metabolic syndrome
and type 2 diabetes, major risk factors for CHD, and
apoCⅢ modulates the metabolism of apoB lipopro-
teins, it is reasonable to hypothesize that apoCⅢ may
affect the relationship between apoB lipoproteins and
CHD risk in clinical studies. Alaupovic et al. report-
ed that the concentration of apoB lipoproteins with
apoCⅢ was the strongest lipoprotein predictor of the
7
progression of coronary atherosclerosis, even in patients
whose LDL cholesterol concentrations were aggres-
sively lowered with lovastatin 20). Another coronary
arteriographic study reported the relationship between
apoCⅢ in apoB lipoproteins and CHD risk 21). The
roles of apoCⅢ and apoE in predicting CHD events
were compared in a large prospective study of patients
with CHD (CARE trial), in which apoCⅢ concentra-
tion in VLDL＋LDL was associated with an increased
risk of CHD regardless of the use of pravastatin 22, 23).
Adjustment for other lipid risk factors did not affect
the results for apoCⅢ, and apoCⅢ was a more specific
marker of atherogenic particles than TG.
Several studies reported that apoCⅢ in HDL was
also associated with CHD in univariate analysis, and
that apoCⅢ concentration in HDL had a positive
rather than inverse correlation with other risk factors,
such as VLDL and triglyceride 24). This suggests that
apoCⅢ exerts atherogenic properties beyond its effect
on apoB lipoprotein metabolism.
Direct Effects of ApoCⅢ on Vascular Cells
The causal association of apoCⅢ with CHD has
been commonly attributed to its inhibitory effect on
the catabolism and clearance of TRLs, prolonging the
plasma residence time of atherogenic TLRs. While this
is undoubtedly true in part, a recent study reported
that apoCⅢ-rich VLDL do not have a longer residence
time than their apoCⅢ-free counterparts 25), since slow
clearance is balanced by rapid lipolytic conversion to
LDL. Indeed, plasma concentrations of apoB lipo-
proteins with apoCⅢ are lower than those without
apoCⅢ. Thus, apoB lipoproteins with apoCⅢ seem to
augment CHD risk out of proportion to their con-
centration in plasma, suggesting that the correlation
between apoCⅢ and CHD risk in population studies
is in part attributable to apoCⅢ’s direct involvement
in atherogenesis; however, the direct effects on vascu-
lar cells of apoB lipoproteins with apoCⅢ specifically
or apoCⅢ itself have been untested. We hypothesized
that apoCⅢ-containing lipoproteins have enhanced
atherogenicity relative to their apoCⅢ-free counter-
parts, and examined the direct effects of apoCⅢ alone
on peripheral blood monocytes and vascular endothe-
lial cells (ECs).
ApoCⅢ Activates Human
Peripheral Monocytes
The adhesion of circulating monocytes to vascu-
lar ECs contributes importantly to the inflammatory
aspects of atherogenesis. We found that apoCⅢ-rich
8 Kawakami and Yoshida

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Fig. 1. ApoCⅢ-rich lipoproteins modulate monocyte adhe- ����� ���βⅡ
sion to endothelial cells.
（This figure was drawn using data taken from reference No. 23, 26, and 27）
(A) Human peripheral monocytes were incubated in the presence
of the indicated lipoproteins (100 μg apoB/mL), apoCⅢ (100 μg/ Fig. 2. Schema depicting the mechanisms by which apoCⅢ
mL) or PBS (Control) for 8 hours, and static adhesion assays to activates monocytes and endothelial cells.
human umbilical vein endothelial cells (HUVECs) were carried
out. ＊p ＜ 0.05 vs. Control, #p ＜ 0.05 vs. VLDL CⅢ− or LDL CⅢ−. ApoCⅢ in TRLs activates PKC families and NF-κB, and increases
(B) Human peripheral monocytes were incubated with PBS (Con- the expression of integrins and adhesion molecules in monocytes
trol), HDL CⅢ＋ or HDL CⅢ− (500 μg chol/mL) for 8 hours, and endothelial cells, causing their interaction. PC-PLC, phospha-
and static adhesion assays to HUVECs were carried out. ＊p ＜ 0.05 tidylcholine-specific phospholipase C.
vs. Control.

VLDL particles (VLDL CⅢ＋), but not VLDL parti- apoE decreased the proadhesive effect. Thus, apoCⅢ
cles without apoCⅢ increase the adhesion of mono- itself but not other apolipoproteins that commonly
cytes to vascular ECs; apoCⅢ protein itself caused this cluster with apoCⅢ on apoB lipoproteins or lipopro-
effect (Fig. 1A) 26), which was observed in a concentra- tein lipids mediate the enhanced monocyte adhesion
tion-dependent manner. Proadhesive concentrations to vascular ECs; however, further study is needed to
of apoCⅢ-containing lipoproteins, 50−100 μg apoB/ determine whether concomitant apoCⅠ, apoCⅡ, or
mL, are well within the range found in fasting plasma, apoE modifies the effects of apoCⅢ on monocyte
e.g. 50 μg apoB/mL in normolipidemic individuals, adhesion.
and ＞100 μg apoB/mL in hypertriglyceridemic indi- We then examined the mechanisms of apoCⅢ-
viduals or those with CHD, supporting their clinical induced monocyte activation. ApoCⅢ alone as well as
relevance. Some HDL preparations can inhibit the VLDL CⅢ＋ activated β1-integrin in monocytes. Pro-
expression of integrins and adhesion molecules in leu- tein kinase C (PKC) plays an important role in several
kocytes and vascular ECs, and reduce their adhesive mechanisms that promote atherosclerosis, including
interaction 27), which is supposed to be one of anti- monocyte-endothelial interaction 28). We showed that
atherogenic properties of HDL. We examined the among PKCs, PKCα plays an important role in mono-
effect of apoCⅢ-rich HDL particles (HDL CⅢ＋) on cyte β1-integrin activation by VLDL CⅢ＋ or apoCⅢ
monocyte adhesion. HDL particles without apoCⅢ itself. We further identified pertussis toxin (PTX)-
(HDL CⅢ−) reduced monocyte adhesion to vascular sensitive G protein-coupled receptors and phosphati-
ECs in a concentration-dependent manner 26), while dylcholine-specific phospholipase C (PC-PLC) as key
HDL CⅢ＋ did not (Fig . 1B). ApoCⅢ might have molecules that activate PKCα, NF-κB and β1-integ-
counteracted potentially atheroprotective actions of rin in monocytes (Fig. 2) 29). Our observations may
other HDL components. Our current data suggest a provide a role for apoCⅢ as a distinct contributor to
novel mechanism for HDL dysfunction induced by inflammation and atherosclerosis through monocyte
apoCⅢ. activation.
ApoCⅢ-containing lipoproteins also contain
other apolipoproteins, such as apoCⅠ, apoCⅡ, and
apoE, as well as various lipids; however, other apolipo- ApoCⅢ Activates Vascular Endothelial Cells
proteins or lipids extracted from apoCⅢ-containing The induction of adhesion molecules in vascular
VLDL did not increase monocyte adhesion. Antibodies ECs and the subsequent recruitment of circulating
against apoCⅢ but not against apoCⅠ, apoCⅡ or monocytes are proinflammatory events that promote
 ApoCⅢ Induces Atherosclerosis
atherogenesis and plaque instability. We demonstrated
that apoCⅢ activates PKCβ rather than PKCα, and
increases the expression of VCAM-1 in non-activated
ECs, thus recruiting the adhesion of monocytes 30).
Moreover, VLDL CⅢ＋, but not VLDL CⅢ−, acti-
vated PKCβ in ECs, and anti-apoCⅢ antibody inhib-
ited PKCβ activation induced by VLDL CⅢ＋, sug-
gesting that apoCⅢ in VLDL plays a pivotal role in
this process (Fig. 1). This study identified NF-κB as
the molecular link between apoCⅢ-induced PKCβ
activation and increased expression of VCAM-1. Since
a portion of TLRs ordinarily contains apoCⅢ31), our
results provide a novel mechanism for vascular EC
activation by TRLs that is independent of lipid moi-
eties and their oxidation in these particles.
ApoCⅢ Induces Insulin Resistance in
Vascular Endothelial Cells and Causes
Endothelial Dysfunction
Endothelial dysfunction importantly contributes
to CHD and is characterized by the reduced bioavail-
ability of nitric oxide (NO), which has potent vasodi-
latory and anti-atherosclerotic properties. Insulin acti-
vates endothelial NO synthase (eNOS) in endothelial
cells and stimulates the production of NO, and insu-
lin resistance in vascular ECs leads to its dysfunction.
Insulin resistance and subsequent endothelial dysfunc-
tion are often seen in diabetes, obesity, and dyslipid-
emia, and major risk factors for CHD, and plasma
apoCⅢ level is high in these conditions. As PKCβ
inhibits insulin signaling in endothelial cells, and
apoCⅢ activates PKCβ in the same cells, we tested the
effect of apoCⅢ on endothelial insulin signaling 32).
ApoCⅢ in VLDL inhibited insulin activation of the
eNOS pathway and the production of NO in vascu-
lar ECs. ApoCⅢ also impaired endothelium-depen-
dent relaxation of mouse aortas. This adverse effect of
apoCⅢ was mediated by PKCβⅡ, which inhibits the
function of IRS-1 (Fig. 3).
Insulin resistance and endothelial dysfunction
associated with hypertriglyceridemia have been attrib-
uted to free fatty acids and other lipid moieties in
TRLs; however, our findings may add a new mecha-
nism that apoCⅢ in TRLs impairs insulin signaling in
vascular ECs, and suggest that apoCⅢ could link dys-
lipidemia with endothelial dysfunction.
Remnant Lipoproteins and ApoCⅢ
ApoCⅢ-rich VLDL or LDL particles are also rich
in apoE as well as TG and cholesterol, which have
similar properties to atherogenic remnant lipoprotein
9
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（Adapted from reference No. 29）
Fig. 3. Schema depicting the mechanisms by which apoCⅢ
causes insulin resistance in vascular endothelial cells.
Insulin resistance in hepatocytes increases apoCⅢ production and
secretion into blood of apoCⅢ. ApoCⅢ in TRLs in turn impairs
insulin-induced NO production by inhibiting IRS-1 function in
vascular endothelial cells. The inhibitory effects of apoCⅢ on NO
production are likely to be mediated by the activation of PKCβⅡ
and partly by ERK, which induce serine phosphorylation of IRS-1.
particles (RLPs) 33). Plasma TRL concentrations, espe-
cially those of RLPs, independently correlate with
atherosclerosis 34, 35). RLPs consist of heterogeneous
TRL particles, and some RLPs have a high content of
apoCⅢ as well as apoE 36). ApoCⅢ-rich VLDL or LDL
particles may be constituents of RLP particles or their
precursors. We reported that several mechanisms of
RLPs directly promoted atherosclerosis 37), in which
RLPs stimulated monocyte adhesion 38), induced the
proliferation of smooth muscle cells 39), and facili-
tated foam cell formation 40). ApoCⅢ may not only be
involved in the formation and accumulation of RLPs,
but may also importantly contribute to these athero-
genic processes by inducing inflammatory processes.
Conclusion
This review described the role of apoCⅢ in the
metabolism of TRLs, and the correlation between
apoCⅢ and CHD risk. We also focused on the direct
effect of apoCⅢ on vascular cells. Many points remain
to be elucidated regarding the precise mechanisms by
which apoCⅢ-rich lipoproteins activate PKCs and
10 Kawakami and Yoshida
NF-κB in vascular cells, although our data suggest
receptors for apoCⅢ other than apoB/E receptor. Fur-
ther studies are also needed to elucidate the kinetics of
apoCⅢ-containing lipoproteins, and their atheroge-
nicity on other types of cells, which will help to
understand the overall atherogenicity of TRLs.
Many previous studies have focused on the roles
of lipid moieties, such as oxidized lipids in atherogenic
lipoproteins; however, our observations may provide
novel insights into the role of apoCⅢ as a direct and
distinct contributor to inflammation and atherosclero-
sis. ApoCⅢ may be a new target for interventions,
particularly in subjects with insulin resistance, meta-
bolic syndrome and type 2 diabetes, because lowering
apoCⅢ not only improved the impaired metabolism
of TRLs in these conditions, but also may directly
contribute to the prevention of atherosclerosis.
Acknowledgements
We thank Makoto Harada for technical assistance.
Grant Support
This study was supported by grants from the
Ministry of Education, Science and Technology
(10178102), ONO Medical Research Foundation,
Takeda Science Foundation, Mitsukoshi Health and
Welfare Foundation, Uehara Memorial Foundation,
and a Sakakibara Memorial Research Grant from the
Japan Research Promotion Society for Cardiovascular
Diseases.
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