Journal of Clinical Lipidology (2015) 9, 384–389

Review Article

Adenosine triphosphate citrate lyase: Emerging

target in the treatment of dyslipidemia
Hern!an N. Lemus, Carlos O. Mendivil, MD, PhD*

Universidad de los Andes Medical School, Bogot!

a, Colombia (Mr Lemus and Dr Mendivil); and Section of Endocrinology,
Department of Internal Medicine, Fundaci!on Santa Fe de Bogot!a, Bogot!a, Colombia (Dr Mendivil)

KEYWORDS: Abstract: Despite major advances in pharmacologic therapy over the last few decades, dyslipidemia
LDL; remains a prevalent, insufficiently recognized, and undercontrolled risk factor for cardiovascular
Lipid metabolism; disease. Statins are the mainstay of hypercholesterolemia treatment, but because of adherence and
Cholesterol; tolerability issues that limit dose titration, there is a need for additional therapies with good efficacy
Hypercholesterolemia; and better tolerability. Adenosine triphosphate (ATP) citrate lyase, a cytoplasmic enzyme responsible
Dyslipidemia; for the generation of acetyl coenzyme A for the de novo synthesis of fatty acids and cholesterol, is a
ATP citrate lyase; very interesting molecular target for the reduction of plasma lipids. Furthermore, ATP citrate lyase in-
AMPK; hibition may be accompanied by activation of 50 -adenosine monophosphate–activated protein kinase, a
ETC-1002; key signaling molecule that acts a central hub in cellular metabolic regulation. ETC-1002 is a small
Statin intolerance molecule inhibitor of ATP citrate lyase that also activates 50 -adenosine monophosphate–activated pro-
tein kinase, effectively reducing low-density lipoprotein cholesterol and inducing some other positive
metabolic changes. Recent evidence from phase I and II clinical trials in humans has shown a positive
efficacy and safety profile of ETC-1002, with low-density lipoprotein cholesterol reductions similar to
those attainable by usual doses of many statins and with no major apparent side effects. These results
potentially introduce a new family of medications that may expand our therapeutic arsenal against
hypercholesterolemia.
! 2015 National Lipid Association. All rights reserved.

Alterations of lipoprotein metabolism are highly preva-
lent risk factors for cardiovascular disease, and their
appropriate treatment has the potential to generate a major
public health impact. There is now abundant evidence to
support the concept that among the different lipoprotein
fractions, tight control of plasma low-density lipoprotein
(LDL) cholesterol (LDL-C) has the most impact on hard
Conflict of Interest: The authors have no conflict of interest to declare.
* Corresponding author. Universidad de los Andes Medical School,
Carrera 7 # 116-05, Of. 413, Bogot!a, Colombia.
E-mail address: carlosolimpo@gmail.com
Submitted October 21, 2014. Accepted for publication January 9, 2015.
outcomes in both primary and secondary cardiovascular
(CV) prevention.1,2
Statins, a family of medications that work as inhibitors
of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA)
reductase (the rate-limiting enzyme in the cholesterol
biosynthesis pathway), are currently the mainstay of hy-
percholesterolemia treatment, and their use has consistently
shown to reduce CV morbidity and mortality.1–3 Despite
the overall safety and efficacy of these medications, statin
intolerance remains a major clinical issue. The most impor-
tant unwanted effects of statins can be grouped into 3 cat-
egories: (1) overt myopathy and/or myalgia, even without
significant elevations of plasma creatine phosphokinase4,5;

1933-2874/! 2015 National Lipid Association. All rights reserved.

http://dx.doi.org/10.1016/j.jacl.2015.01.002
Lemus and Mendivil ATP citrate lyase inhibition
(2) asymptomatic increases in liver transaminases4,6; and
(3) an increase in the risk of developing type 2 diabetes
mellitus, or a slight impairment in glycated hemoglobin
A1c among patients already diagnosed with type 2 diabetes
mellitus.7,8 Although these adverse effects are only seldom
severe or life threatening, they do compromise patient
adherence or treatment continuation and therefore the ex-
pected CV benefit of therapy.
Furthermore, despite the wide availability and clinical
use of statins, the percentage of patients who reach LDL-C
goals remains worryingly low.9,10 This may be related to
the dose-dependent nature of statin-related adverse effects,
which prevents strict dose escalation when necessary.4 To
overcome the limitations inherent to statin intolerance,
and to provide patients with the full benefit that can be
derived from LDL-C reduction, new families of
cholesterol-lowering medications are being developed,
exploiting molecular targets different from HMG-CoA
reductase. One such pharmacologic family is proprotein
convertase subtilisin/kexin type 9 (PCSK9) inhibitors, but
concerns still remain about subcutaneous administration,
cost, and the potential for neurocognitive side effects.11
Recently, an entirely new approach to cholesterol lowering
has been developed.
Adenosine triphosphate citrate lyase and its
role in lipid synthesis
Adenosine triphosphate (ATP) citrate lyase (ACL) is a
cytosolic enzyme most highly expressed in lipogenic
tissues such as liver and white adipose tissue.12 ACL cata-
lyzes a reaction in which 2 carbons from citrate are trans-
ferred to CoA, with consumption of 1 ATP molecule and
generation of acetyl CoA and oxaloacetate. ACL is thus a
major contributor to the cytosolic pool of acetyl CoA, the
fundamental building block for the biosynthesis of both
fatty acids and cholesterol. X-ray diffraction analyses of
ACL have revealed that it is conformed by 4 polypeptide
chains of similar size.13 Recent studies have identified the
binding site of both citrate and ATP to ACL, as well as
two thirds of the enzyme’s complete 3-dimensional struc-
ture.14 The ACL gene is under transcriptional regulation
by sterol regulatory element binding protein 1 (SREBP-
1).15 The mature protein seems to be stabilized by
posttranslational phosphorylation of specific serine and
threonine residues,16 although the relevance of these mod-
ifications has not been tested in vivo.
In liver, the essential organ of lipoprotein synthesis,
ACL plays a fundamental role in lipogenesis and steroido-
genesis by supplying cytosolic acetyl CoA to both path-
ways. By using a tricarboxylic acid cycle intermediate
(citrate) to produce acetyl CoA, ACL can be seen as an
important bridge between carbohydrate and lipid meta-
bolism. Intramitochondrial citrate is transported via the
so-called citrate shuttle to the cytosol, where it encounters
ACL (Fig. 1). Acetyl-CoA carboxylase (ACC—the rate-
385
Figure 1 Crucial role of ACL as a precursor supplier for both
fatty acid and cholesterol synthesis. ACC, acetyl-CoA carbox-
ylase; ACL, ATP citrate lyase; ATP, adenosine triphosphate;
CoA, coenzyme A; HMG, hydroxymethylglutaryl; TCA, tricar-
boxylic acid.
limiting enzyme in de novo fatty acid biosynthesis) carbox-
ylates acetyl CoA to produce malonyl CoA. Then, through
repetitions of the 4-reaction cycle of de novo lipogenesis,
palmitic acid is synthesized. Modifications of this primary
product lead to other (shorter, longer, or unsaturated) fatty
acids.17 Depending on the set of biosynthetic enzymes that
is predominantly expressed, acetyl CoA from ACL can also
be used for cholesterol synthesis: HMG-CoA is formed by
condensation of acetyl CoA and acetoacetyl CoA (cata-
lyzed by HMG-CoA synthase) and later reduced by
HMG-CoA reductase to mevalonate.18 Mevalonate is then
converted into 3-isopentenyl pyrophosphate by 3 consecu-
tive reactions requiring ATP. Multiple extension steps
involving iterative addition of extra 5-carbon modules leads
to squalene, which is cyclized to form lanosterol. The
removal of 3 methyl groups plus reduction of one double
bond and migration of another double bond in lanosterol
finally yields cholesterol (Fig. 1).
ACL and AMPK have opposite effects on lipid
biosynthesis
The enzyme 50 -adenosine monophosphate–activated
protein kinase (AMPK) is a serine/threonine kinase that
works as a sensor for cellular depletion of ATP, whose
activation results in the simultaneous shutting down of
several energy-consuming pathways and in the activation of
energy-generating pathways. Activation of the AMPK
pathway also influences a plethora of cellular functions
through phosphorylation of other enzymes and transcription
factors, which ultimate leads to changes in expression of
multiple genes.19 Among these target genes are the rate-
limiting enzymes for steroidogenesis and fatty acid synthe-
sis (HMG-CoA reductase and ACC), but also enzymes with
a crucial role in gluconeogenesis and liver glucose produc-
tion, phosphoenolpyruvate carboxykinase and glucose-6-
phosphatase. The role of AMPK in lipid metabolism also
386
involves regulation of mitochondrial long-chain fatty acids
oxidation. Malonyl CoA, the product of ACC, is a strong
inhibitor of carnitin-palmitoil transferase 1 (CPT-1), an
enzyme responsible for fatty acid transport into the mito-
chondrial matrix for their subsequent beta-oxidation.20
Phosphorylation of ACC by AMPK reduces malonyl CoA
production in the vicinity of CPT-1, resulting in its disinhi-
bition and in increased transport and oxidation of long-
chain fatty acids.21 Thus, ACL activation provides the
building blocks for fatty acid biosynthesis, whereas
AMPK activation stimulates their degradation.
Inhibition of ACL
Among several ACL inhibitors that were initially tested,
ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecaned–
ioic acid) is the one currently in a most advanced stage of
clinical development. The molecule was first reported in
2004 as ESP55016, after a search for long-chain hydrocar-
bon derivatives with positive effects on lipid and/or
metabolic profiles in vivo. Initial experiments demonstrated
the ability of ETC-1002 to inhibit fatty acid and sterol
synthesis and to stimulate palmitate oxidation in primary
rat hepatocytes, as well as to lower plasma non–high-
density lipoprotein (HDL) cholesterol (HDL-C), triglycer-
ides, and free fatty acids in a rat model of obesity and
metabolic syndrome (fa/fa).22 Furthermore, in this initial
set of experiments, ETC-1002 also reduced weight gain
and insulin resistance, as reflected by lower fasting levels
of both serum insulin and glucose. No direct effect of
ACL inhibition on HMG-CoA reductase levels or activity
was observed. The increase in fatty acid oxidation was
CPT-1 dependent, but the degree of AMPK or ACC phos-
phorylation did not change significantly, suggesting that
ETC-1002 increased CPT-1 only through reduced malonyl
CoA availability. Nonetheless, more recent studies in chow-
fed rats did find an increase in phospho-AMPK and
phospho-ACC after 2 weeks of treatment with ETC-1002
(30 mg/kg/d), and also a transient (10 min) increase in
phosphorylation of AMPK, ACC, and HMG-CoA reductase
in primary hepatocytes in vitro.23 ETC-1002 inhibits de
novo sterol and fatty acid synthesis in primary rat hepato-
cytes, inducing dose-dependent reductions cellular acetyl
CoA, malonyl CoA, and HMG-CoA, and simultaneously
increasing cellular citrate. These changes start to occur
just 5 minutes after administration of the drug.23
As cytosolic acetyl-CoA levels in hepatocytes descend,
cellular production and concentration of cholesterol go
down, a change that is known to be sensed by the Sterol
response element binding protein (SREBP)/Cleavage-
Activating Protein system, leading to SREBP escort to the
Golgi apparatus, cleavage, and nuclear translocation.24 In the
nucleus, SREBPs binds to sterol response elements in several
target genes, regulating their transcription. One of those
genes is the LDL receptor (LDLR) gene, whose increased
expression leads to increased uptake of circulating LDL
Journal of Clinical Lipidology, Vol 9, No 3, June 2015
and lowering of plasma LDL-C.25 Expression of the gene
for HMG-CoA is also stimulated, but in the context of low
cytosolic acetyl CoA, this does not impact cholesterol pro-
duction. Activation of AMPK via liver kinase B1 (LKB1)
by ETC-1002 leads to inhibition of ACC and HMG-CoA
reductase (Fig. 2) and could potentially increase nitric oxide
production23 and reduce inflammatory and oxidative stress.26
The pharmacokinetics of ETC-1002 seem to make it
suitable for once-daily administration. MacDougall et al27
reported in a phase I study that used doses between 20
and 220 mg/d, a directly proportional increase in the
maximum plasma concentration and 24-hour area under
the curve with increasing doses of ETC-1002. The mean
half-life of the drug ranged between 16 and 33 hours across
the dosing range.
Given that ETC-1002 would be used in patients with
comorbidities, many of which may also be receiving
a statin, a clinical trial was undertaken, aimed at evaluating
the safety and pharmacokinetic interactions of ETC-
1002 in patients with hypercholesterolemia who were
Figure 2 Mechanism of action of the ATP citrate lyase (ACL)
inhibitor ETC-1002 as a hypolipidemic agent. Direct inhibition
of ACL by ETC-1002 lowers cytosolic acetyl CoA, reducing sub-
strate availability for acetyl-CoA carboxylase (ACC) and therefore
malonyl-CoA levels. Lower malonyl-CoA levels have 2 conse-
quences: reduced de novo fatty acid synthesis (FAS) and derepres-
sion of carnitin-palmitoil transferase 1 (CPT-1), which increases
fatty acid transport into the mitochondrial matrix to undergo
beta-oxidation. Less acetyl CoA is also available for
hydroxymethylglutaryl-CoA (HMG-CoA) synthesis, effectively
reducing flow through the cholesterol biosynthesis pathway. In
addition, 50 -adenosine monophosphate–activated protein kinase
(AMPK) activation by ETC-1002 reduces the activity of ACC
and HMG-CoA reductase, the rate-limiting enzymes of fatty
acid and cholesterol synthesis, respectively. The reduction in intra-
cellular cholesterol levels stimulates membrane expression of
LDLR, augmenting LDL uptake and reducing plasma LDL.
ATP, adenosine triphosphate; CoA, coenzyme A; LDL, low-
density lipoprotein; LDLR, LDL receptor; TCA, tricarboxylic
acid.
Lemus and Mendivil ATP citrate lyase inhibition 387

Table 1 Clinical trials of ETC-1002

Placebo-subtracted
percentage
Ref Participants Doses used (mg/d) LDL-C change Comments
27
56 healthy subjects, 6 per dose 20 NS Dose-finding phase I study. No
group 1 8 in placebo group, 60 211.2 relevant adverse effects.
93% male 100 216.5
120 215.0
140 221.3
180 227.1
220 236.1
25
177 patients with LDL-C 130- 40 216 No significant change in HDL-C
220 mg/dL 80 223 or triglycerides. Similar results
120 225 among patients with or without
high triglycerides.*
31
60 patients with type 2 diabetes, Forced titration, 239 No significant change in HDL-C
mean LDL-C 126 mg/dL. 2 wks 80 mg/d and or triglycerides, 41% reduction
2 wks 120 mg/d in hsCRP*
32
56 patients with hypercholester 60 Up to 32%
olemia and a history of statin 120
intolerance 180
240
32
58 patients with hypercholester 60 Up to 22%
olemia, ETC-1002 used as add-on 120
to 10 mg/d atorvastatin 180
240
32
Patients with hypercholesterol 120 Up to 30% in monotherapy;
emia, with or without statin 180 up to 48% 1 ezetimibe
intolerance 120 1 ezetimibe
180 1 ezetimibe
HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; NS,
nonsignificant; Ref, reference.
*The rate of adverse events was not significantly different from placebo.

concomitantly receiving atorvastatin 10 mg (clinicaltrials.
gov NCT01779453). According to preliminary results
announced by the manufacturer, ETC-1002 showed only
a small pharmacokinetic interaction with atorvastatin.
Several other compounds have proven capable of
inhibiting ACL in vitro, including (2), (2), 2,2 difluoroci-
trate, several benzonesulfonamides, and the naturally
occurring compound hydroxycitrate. Nevertheless, their
development as pharmacologic agents has been limited by
issues related to poor ability to cross cell membranes, poor
affinity for ACL requiring too high tissue concentrations,
or, as in the case of hydroxycitrate, poor specificity leading
to undesirable inhibition of other essential enzymes (iso-
citrate dehydrogenase).28 The compound bb’-methyl-
substituted a,w-dicarboxylic acid of 16-carbon length
(MEDICA 16) was identified as a potent inhibitor of neutral
lipid synthesis in the rat,29 with additional direct inhibitory
activity over acyl-CoA carboxylase.30 However, MEDICA
16 did not continue its development into the clinical phase.
Yet, other studies have evaluated ACL inhibitor pre-
cursors that can penetrate the plasma membrane, including
SB-204990, the lactone prodrug of the ACL inhibitor SB-
201076. In HepG2 cells, SB-204990 strongly inhibited both
cholesterol and fatty acid synthesis.22 In rats, the compound
also reduced plasma cholesterol and very low–density lipo-
protein production, albeit to a smaller extent than in vitro.
In dogs, the effect of SB-204990 on plasma triglycerides
and cholesterol was still more modest, yet still significant.22
Clinical efficacy of ACL inhibition
There is currently a quite efficacious and extensively
used family of LDL-lowering medications, the HMG-CoA
reductase inhibitors, commonly referred to as statins.
Despite their efficacy, many patients do not reach LDL
treatment goals because titration of statin doses may lead to
dose-dependent adverse effects.4–8 Against the backdrop of
this unmet need, a number of studies have evaluated the
ACL inhibitor ETC-1002 as a lipid-lowering agent in hu-
mans. Table 1 recapitulates the key features and results of
clinical phase I and phase II studies involving ETC-1002.
The lowest dose of ETC-1002 with a significant LDL-C
reducing effect has been 60 mg/d, and the maximum dose
tested so far for clinical efficacy is 240 mg/d (Table 1).
In adult patients with hypercholesterolemia, ETC-1002
388 Journal of Clinical Lipidology, Vol 9, No 3, June 2015

Table 2 Adverse events observed with ETC-1002 in 2 published clinical trials using different doses
25 25 25 31
Reference number
Daily dose of ETC-1002 40 mg 80 mg 120 mg 2 wk 80 mg
and then 2
wk 120 mg
Number of patients receiving this dose 45 44 44 30
Patients with any adverse event in ETC-1002 group, n (%) 34 (76) 32 (73) 31 (71) 14 (47)
Patients with any adverse event in placebo group, n (%) 33 (75) 33 (75) 33 (75) 21 (70)
Serious adverse events 0 0 0 —
Discontinuation because of adverse events in ETC-1002 group, n (%) 3 (7) 4 (9) 3 (7) 0
Discontinuation because of adverse events in placebo group, n (%) 4 (9) 4 (9) 4 (9) 1 (3)
Headache, n (%) 5 (11) 5 (11) 7 (16) 6 (20)
Dry eyes, n (%) — — — 2 (7)
Viral upper respiratory infection — — — 2 (7)
Abdominal pain — — — 0
Arthralgia, n (%) 2 (4) 2 (5) 1 (2) 2 (7)
Pruritus, n (%) — — — 1 (3)
Constipation, n (%) — — — 2 (7)
Dizziness — — — 0
Nausea, n (%) 3 (7) 3 (7) 4 (9) 0
Urinary tract infection, n (%) 4 (9) 1 (2) 0 —
Diarrhea, n (%) 3 (7) 3 (7) 1 (2) —
Fatigue, n (%) 3 (7) 1 (2) 1 (2) —
Cough, n (%) 2 (4) 3 (7) 1 (2) —
Myalgia, n (%) 2 (4) 2 (5) 3 (7) 0
Bronchitis, n (%) 0 3 (7) 1 (2) —
Pain in extremity, n (%) 0 0 4 (9) —
AST/ALT . 3 ! ULN, n (%) 0 1 (2) 0 —
CK . 5 ! ULN 0 0 0 —
AST, aspartate amino transferase; ALT, alanine amino transferase; CK, creatine kinase; ULN, upper limit of normal.

has induced dose-dependent LDL-C reductions between
16% and 25%, regardless of plasma triglycerides.25
Non–HDL-C (18%-27%) and plasma apolipoprotein B
(15%-22%) were reduced to a similar degree, whereas
plasma triglycerides were reduced nonsignificantly and
only by the 40 mg (15%) and 80 mg (12%) doses. Levels
of lipoprotein(a) were completely unaltered with any of
the doses of ETC-1002 in this study. An even more marked
hypocholesterolemic effect was observed in a study that
included only patients with type 2 diabetes and hypercho-
lesterolemia31; a 4-week treatment course reduced LDL-C
levels by 39% on average, with a simultaneous reduction
of circulating high-sensitivity C-reactive protein of 41%.
Non–HDL-C was reduced by 20%, with no significant
changes in HDL-C or triglycerides. This increased efficacy
in the context of insulin resistance and/or type 2 diabetes
may be related to activation of the AMPK pathway by
ETC-1002.
Preliminary results of studies sponsored by the manu-
facturer of ETC-1002 have also shown positive results for
monotherapy in statin-intolerant patients and for the com-
bined use of the ACL inhibitor plus other cholesterol-
reducing agents. In patients with a documented history
of intolerance to statins, ETC-1002 60 to 240 mg/d has
reduced plasma LDL-C up to 32%.29 Addition of the new
agent in the same dose range to 10 mg/d of atorvastatin
has provided an additional LDL-C reduction of up to
22%. Similarly, combined use with ezetimibe 10 mg/d
has lowered LDL-C levels up to 48% (180 mg of ETC-
1002 plus 10 mg of ezetimibe), an effect similar to that ob-
tained with substantial doses of most available statins.
In all clinical studies undertaken so far, the rate of
adverse effects and/or discontinuation in the ETC-1002
treatment groups has been equal to or lower than that in the
placebo group of each study. This was also true in the
patients with a documented history of intolerance to statins,
suggesting that muscle-related adverse events are not
necessarily a direct consequence of reductions in LDL-C,
but instead an effect related to other properties of statins as
a pharmacologic group. Treatment with ETC-1002 has not
increased plasma levels of liver transaminases, creatine
kinase, bilirubin, or creatinine (Table 2).
Conclusions
There is currently a need for cholesterol-lowering drugs
that can be used to replace statins in intolerant patients or to
complement their effect when treatment goals are not
reached. Given its central role in modulating availability
of the key substrate for cellular lipid synthesis, ACL is a
very attractive target for the development of such agents.
ETC-1002 is currently the ACL inhibitor whose clinical
Lemus and Mendivil ATP citrate lyase inhibition
development program is most advanced. ETC-1002 is also
an AMPK activator, an additional molecular target that
potentially expands the impact provided by ACL inhibition
by modulating fatty acid oxidation and carbohydrate
metabolism. Despite the small number of patients studied
so far, results of clinical trials with the new agent look
promising and validate the mechanism, possibly paving the
way for a new family of hypolipidemic drugs.
Further studies are needed to test whether ACL inhibition
and/or AMPK activation will reduce systemic inflammation
and ameliorate other metabolic disturbances beyond pure
hypercholesterolemia, to assess the benefits and risks of its
use in the long term, and to fully characterize the
pharmacokinetics and drug interaction profile of ETC-1002.
Acknowledgments
Both authors contributed equally to the literature search,
article selection, analysis of the information, and writing
and revision of the article. Both authors approved the final
version of this article and its submission.
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