Mitochondrial CPT1A: Insights into structure, function, and basis for drug development

Abstract

Carnitine Palmitoyl-Transferase1A (CPT1A) is the rate-limiting enzyme in the fatty acid β-oxidation, and its deficiency or abnormal regulation can result in diseases like metabolic disorders and various cancers. Therefore, CPT1A is a desirable drug target for clinical therapy. The deep comprehension of human CPT1A is crucial for developing the therapeutic inhibitors like Etomoxir. CPT1A is an appealing druggable target for cancer therapies since it is essential for the survival, proliferation, and drug resistance of cancer cells. It will help to lower the risk of cancer recurrence and metastasis, reduce mortality, and offer prospective therapy options for clinical treatment if the effects of CPT1A on the lipid metabolism of cancer cells are inhibited. Targeted inhibition of CPT1A can be developed as an effective treatment strategy for cancers from a metabolic perspective. However, the pathogenic mechanism and recent progress of CPT1A in diseases have not been systematically summarized. Here we discuss the functions of CPT1A in health and diseases, and prospective therapies targeting CPT1A. This review summarizes the current knowledge of CPT1A, hoping to prompt further understanding of it, and provide foundation for CPT1A-targeting drug development.

Full text

Mitochondrial CPT1A: Insights
into structure, function, and basis
for drug development
Kai Liang*
School of Life Science, Peking University, Beijing, China
Carnitine Palmitoyl-Transferase1A (CPT1A) is the rate-limiting enzyme in the fatty
acid β-oxidation, and its deficiency or abnormal regulation can result in diseases
like metabolic disorders and various cancers. Therefore, CPT1A is a desirable drug
target for clinical therapy. The deep comprehension of human CPT1A is crucial for
developing the therapeutic inhibitors like Etomoxir. CPT1A is an appealing
druggable target for cancer therapies since it is essential for the survival,
proliferation, and drug resistance of cancer cells. It will help to lower the risk
of cancer recurrence and metastasis, reduce mortality, and offer prospective
therapy options for clinical treatment if the effects of CPT1A on the lipid
metabolism of cancer cells are inhibited. Targeted inhibition of CPT1A can be
developed as an effective treatment strategy for cancers from a metabolic
perspective. However, the pathogenic mechanism and recent progress of
CPT1A in diseases have not been systematically summarized. Here we discuss
the functions of CPT1A in health and diseases, and prospective therapies targeting
CPT1A. This review summarizes the current knowledge of CPT1A, hoping to
prompt further understanding of it, and provide foundation for CPT1A-
targeting drug development.
KEYWORDS
CPT1a, FATTY ACID β-OXIDATION, cancer, inhibitor, drug development
Introduction
Globally, the prevalence of obesity has increased, and more and more attention has been
paid to lipid metabolism (Bluher, 2019). Fatty acid oxidation (FAO), a process that occurs
within cells, is an important energy source. Diabetes patients cannot use sugar as their
primary source of energy since they have poor insulin sensitivity (Shepherd and Kahn, 1999).
Additionally, the majority of cancer cells use lipid metabolism as a source of energy (Munir
et al., 2019). Reducing or inhibiting FAO can turn off the energy source of cancer cells and
starve them to death (Bergers and Fendt, 2021).
The majority of FAO happens in mitochondrion. Long chain fatty acids (LCFAs) cannot
directly enter the mitochondrial inner membrane, and CPT1A is required to convert acyl-
CoA (carbon chain longer than 12) into acyl-carnitine (Ceccarelli et al., 2011). CACT
(carnitine/acylcarnitine carrier protein), a transporter in the inner mitochondrial
membrane, transports free carnitine out of the mitochondrial matrix and into the
cytoplasm as well as acyl-carnitine into the mitochondrial matrix (Indiveri et al., 2011).
Acyl-carnitine entering the mitochondrial matrix is again converted to acyl-CoA by
CPT2 and participates in the true fatty acid β-oxidation cycle (Indiveri et al., 2011).
OPEN ACCESS
EDITED BY
Jing Wu,
Shandong Provincial Qianfoshan
Hospital, China
REVIEWED BY
Chunming Cheng,
The Ohio State University, United States
Chao Sun,
The Second Hospital of Shandong
University, China
*CORRESPONDENCE
Kai Liang,
liangkai@pku.edu.cn
SPECIALTY SECTION
This article was submitted to
Experimental Pharmacology and Drug
Discovery,
a section of the journal
Frontiers in Pharmacology
RECEIVED 07 February 2023
ACCEPTED 13 March 2023
PUBLISHED 23 March 2023
CITATION
Liang K (2023), Mitochondrial CPT1A:
Insights into structure, function, and basis
for drug development.
Front. Pharmacol. 14:1160440.
doi: 10.3389/fphar.2023.1160440
COPYRIGHT
© 2023 Liang. This is an open-access
article distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original author(s)
and the copyright owner(s) are credited
and that the original publication in this
journal is cited, in accordance with
accepted academic practice. No use,
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which does not comply with these terms.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 23 March 2023
DOI 10.3389/fphar.2023.1160440

CPT1A is a rate-limiting enzyme of FAO that catalyzes the
transfer of the long-chain acyl group in acyl-CoA ester to carnitine,
allowing fatty acids to enter the mitochondrial matrix for oxidation
(Figure 1)(Houten et al., 2016).
CPT1 was originally identified by McGarry and Foster in
1978, and they hypothesized that CPT1 is the rate-limiting
enzyme in fatty acid oxidation (McGarry et al., 1978). CPT1A
can be divided into three isoforms, known as CPT1A, CPT1B,
and CPT1C, based on its tissue distribution, and sequence
characteristics. CPT1A is extensively expressed in the liver,
kidney, pancreas, adipose tissue, lymphocytes, and fibroblast,
while CPT1B and CPT1C have strict tissue-specific
distributions (Bonnefontetal.,2004). CPT1A has a higher
affinity for carnitine (Km = 30 μM for ratCPT1A) than CPT1B
(Km = 500 μMforratCPT1B)(Ramsay et al., 2001;Ceccarelli
et al., 2011). Both CPT1A and CPT1B have significant effects on
the metabolic syndrome, cardiovascular disease, type
2 diabetes, and other disorders (Bonnefontetal.,2004).
Human CPT1A and CPT1B share 63% of their total
sequence homology, 82% around the active region (Figure 2)
(Ceccarelli et al., 2011). CPT1C is mostly found in the
hypothalamus and hippocampus, where it can control
ceramide levels and influence learning, cognition (Virmani
et al., 2015). Although CPT1C can bind malonyl-CoA, it has
low catalytic activity, making functional investigations difficult
FIGURE 1
Chart showing how the CPT shuttle system transports palmitoyl-
CoA into the mitochondria. The carnitine shuttle system includes
CPT1A, CACT, and CPT2. Mitochondrial fatty acid β-oxidation (FAO) is
started by the successive actions of CPT1A (in the outer
membrane) and CPT2 (in the inner membrane), together with a
carnitine-acylcarnitine translocase (CACT).
FIGURE 2
Multiple sequence alignment was performed by ClustalW in MEGA11 software (Tamura et al., 2021) and further treated by ESPript webserver (Robert
and Gouet, 2014). Sequence alignment of three CPT1 isoforms with strictly conserved amino acid residues highlighted in box.
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(Fado et al., 2021). Spastic paraplegia, which is exclusive to
CPT1C and has nothing in common with CPT1A deficiency, is
most likely caused by a dominant genetic variant in CPT1C
(Rinaldi et al., 2015).
CPT1A gene encodes a protein with 773 amino acids, which is a
transmembrane protein located in the outer membrane of
mitochondria facing the cytoplasm (Ramsay et al., 2001). Two
transmembrane helical regions divide CPT1A protein into the
small N-terminal regulatory region (about 47 amnio acids) and
the main C-terminal catalytic domain (Gobin et al., 2003). Near the
N-terminal region of CPT1A, two transmembrane helices act as an
anchor to the mitochondrial outer membrane. The majority of the
N- and C-termini are located on the cytoplasmic side, leaving just a
loop of about 27 amino acid residues at the N-terminus in the inner
and outer membrane space (Figure 3)(Fraser et al., 1997).
The basic state of CPT1A is a trimer, which has the potential to
further merge into a hexamer, and may play a role in the sensitivity
to malonyl-CoA (Faye et al., 2007). CPT1A, together with acyl-CoA
synthetase (ACSL) and voltage-dependent anion channel (VDAC)
form the fatty acid transfer complex located in the outer membrane
(Lee et al., 2011).
So far, it is difficult to find a membrane (or membrane-like)
condition that can maintain the enzyme activity of CPT1 to make
the protein soluble, let alone to study the structure of this enzyme.
Despite characterization of the ratCPT2 crystal structure, the
sequence similarity with CPT1A is low, making it of little use as
a reference for CPT1A structure research (Gobin et al., 2003).
Structure of CPT1A
CPT1A was discovered in 1978 as the result of a gene located at
11q13.3 that comprises 22 exons and belongs to the carnitine/
choline acetyltransferase family (McGarry et al., 1978). The
CPT1A gene codes for a 773 amino acid protein that has a
short N-terminal regulatory domain (residues 1–47), a
mitochondrial intermembrane domain (residues 74–102), two
transmembrane (TM) domains (residues 48–73 for TM1 and
residues 103–122 for TM2), and a catalytic domain (residues
123–773). A conformation shift in the N-terminal region is
critical in malonyl-CoA-mediated enzyme activity control (Rao
et al., 2011).
CPT1A can be homo-oligomerized to form trimers (Figure 4),
which further form hexamers (Faye et al., 2007;Jenei et al., 2009).
It has been suggested that the interaction between the GXXXG
and GXXXA motifs in CPT1A TM2 helix is essential for
its oligomerization (Jenei et al., 2009). Another study revealed
that long chain acyl-CoA synthetase 1 (ACSL1) and the voltage-
dependent anion channel (VDAC) were also immunocaptured
by CPT1A antibodies, suggesting that CPT1A, ACSL1, and
VDAC may all be members of mitochondrial outer
membrane acylcarnitine translocation complex (Lee et al.,
2011). Regarding the oligomerization of CPT1A, both models
have a justification for existing due to the lack of structural
support, and further (in situ) structural studies are needed to
resolve this issue.
FIGURE 3
Molecular properties and physiological functions of CPT1A. (A) Domain structure of the full-length CPT1A; Two transmembrane helical regions
(TM1 and TM2) divide CPT1A protein into the small N-terminal regulatory region (about 47 amnio acids) and the main C-terminal catalytic domain. (B)
Dual physiological functions of CPT1A.
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Physiological functions of CPT1A
Succinylation
Lysine succinylation is a newly identified protein post-
translational modification (Zhang et al., 2011). CPT1A is one
of four well-known succinylation regulators including CPT1A,
lysine acetyltransferase 2A (KAT2A), Sirtuin5 (SIRT5) and
Sirtuin7 (SIRT7) (Wang et al., 2017;Kurmi et al., 2018;Lu
et al., 2021). CPT1A mutant H473A (key acyl-CoA binding
site) loses all acylation activity; mutant G710E loses the
carnitine palmitoyl-transferase activity, however, maintains its
succinylation activity, suggesting that Gly710 is very important
for CPT1A succinyl-transferase activity (Kurmi et al., 2018).
CPT1A can modulate the succinylation of enolase 1 to
enhance the growth of breast cancer (Kurmi et al., 2018)and
the succinylation of S100A10 to facilitate the spread of gastric
cancer (Wang et al., 2019).
CPT1A in iTreg cell differentiation
Inducible regulatory T (iTreg) cells are critical for immune
suppression and maintains the immune homeostasis
(Josefowicz et al., 2012;Savage et al., 2013). Butyric acid can
be processed to butyryl-CoA, which competes with malonyl-
CoA at His473 to release CPT1A activity for FAO, thereby
inducing inducible regulatory T cell (iTreg cell)
differentiation via Butyric acid- Butyryl CoA—CPT1A axis
(Hao et al., 2021).
Regulation of CPT1A
The balance of lipid metabolism is crucial for maintaining
homeostasis, making it crucial to control CPT1A, the key enzyme
of FAO. Genetic, physiological, and dietary modulators are all
involved in the regulation of CPT1A (Figure 5).
Transcriptional regulation of CPT1A
PPARαProliferative activated receptor α(PPARα) can greatly
enhance CPT1A expression (Kersten et al., 1999). The transcriptional
coactivator PPAR gamma coactivator 1α(PGC-1α) cooperates with
PPARαto modulate CPT1A in the liver (Jackson-Hayes et al., 2003).
Besides, the regulation of CPT1A by Leucine-rich repeat kinase 2
(LRRK2) may be through the activation of AMP-activated protein
kinase (AMPK) and PPARα(Lin et al., 2020).
FGF21 The PPARα-fibroblast growth factor 21 (FGF21) axis
was activated in the liver of CPT1A deficient mice, which could be
used to avoid inflammation, insulin resistance, and weight gain
(Sun et al., 2021). Besides, FGF21 could promote CPT1A
expression and FAO in β-cells by activating the AMPK-ACC
(acetyl-CoA carboxylase) pathway and PPAR δ/γsignaling axis
(Xie et al., 2019).
PGC-1αPGC1αbinds to CCAAT/enhancer binding protein β
(CEBPB) to enhance CPT1A transcription, resulting in activation of
FAO through PGC1α/CEBPB/CPT1A/FAO signaling axis, which
can promote radiation resistance of nasopharyngeal carcinoma
(NPC) (Du et al., 2019).
MiRNA regulation of CPT1A
MiR-33a/b Several genes involved in fatty acid metabolism
including CPT1A, HADHB contain predicted binding sites for
miR-33a/b (Davalos et al., 2011). Overexpression of miR-33a/b
can reduce FAO by downregulating CPT1A and lead to the
accumulation of triglycerides in human hepatic cells (Davalos
et al., 2011).
MiR-124 Downregulation of CPT1A expression by miR-124,
limiting the conversion of long-chain acyl-CoA moieties to long-
chain acylcarnitine (Valentino et al., 2017).
MiR-328-3p CPT1A is a downstream target of miR-328-3p in
breast cancer, and miR-328-3p overexpression suppresses cancer
spread by interfering with FAO via CPT1A (Zeng et al., 2022). The
MiR-328-3p-CPT1A-FAO pathway is crucial for the metastasis of
FIGURE 4
CPT1A homo-trimer structure predicted by ClusPro online server (https://cluspro.org/). (A) Top view of CPT1A trimer; (B) Bottom view of CPT1A
trimer with transmembrane region highlighted by yellow circle; (C) Side view of CPT1A trimer located on mitochondrial outer membrane.
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breast cancer, and miR-328-3p upregulation can be used for
reducing metastasis in breast cancer patients (Zeng et al., 2022).
MiR-370 The liver miR-370 plays a significant role in the
inhibition of CPT1A gene expression, which can directly affect
its target gene CPT1A, suppressing its expression and lowering
FAO efficacy (Iliopoulos et al., 2010).
Hormone regulation of CPT1A
Hormones can affect CPT1A in organs like the heart, liver, and
muscle. Several hormones can take involvement in CPT1A
expression and enzyme activity control.
Insulin Insulin can significantly lower the expression of CPT1A
and increase its sensitivity to malonyl-coA (Park et al., 1995). By
controlling CPT1A expression and enzyme activity, insulin can limit
FAO and gluconeogenesis in order to lower blood sugar level, which
is also one of the mechanisms to treat diabetes.
Thyroxine Thyroxine, a different hormonal modulator, has a
significant impact on FAO in the liver. CPT1A mRNA could rise by
five times with thyroxine supplementation, but mRNA in
hypothyroid rats decreased (Heimberg et al., 1985).Thyroxine can
increase CPT1A expression by interacting with the thyroid response
elements (TRE) in the CPT1A promoter, (Mynatt et al., 1994).
Thyroxine can also assist in the upregulation of the CPT1A gene by
increasing PGC-1αmRNA and protein levels in hepatocytes (Zhang
et al., 2004).
ERRαEstrogen-Related Receptor-α(ERRα), which belongs to
the nuclear receptor subfamily, is a viable target for NAFLD and that
the ERRαagonist may serve as an intriguing pharmacological option
for management of metabolic diseases (Mao et al., 2022). ERRα
reduces the thyroid hormone-induced expression of CPT1A and
mitochondrial FAO via PGC1α(Singh et al., 2018). Inhibition of
ERRαwith XCT790 treatment can increase the expression of
CPT1A, further promoting lipid metabolism (Michalek et al., 2011).
Adiponectin Adiponectin, an adipose-secreted protein that has
been linked to insulin sensitivity, plasma lipids, and inflammatory
patterns, is an established biomarker for metabolic health
(Aslibekyan et al., 2017). Adiponectin phosphorylates and
triggers AMPK, which modulates CPT1A via the AMPK-ACC-
CPT1A pathway (Li et al., 2007). The acetyl-CoA carboxylase
(ACC)/malonyl-CoA pathway could be strongly blocked by
phosphorylated AMPK, thus increasing the activity of the CPT1A
enzyme. Besides, CPT1A methylation is associated with circulating
adiponectin levels, likely in an obesity-dependent manner, which
can be a novel pleiotropic marker of chronic disease risk (Aslibekyan
et al., 2017).
Metabolite regulation of CPT1A
Long chain fatty acid (LCFA) LCFA is a substrate for CPT1A and
one natural ligand of PPARα(Nakamura et al., 2014). It can up-
regulate CPT1A by directly acting on peroxisome proliferator
response elements (PPREs) in CPT1A introns, as well as via
activating PPARα(Chatelain et al., 1996;Le May et al., 2005).
Malonyl-CoA Malonyl-CoA is produced by acetyl-CoA
carboxylase2 (ACC2) during fatty acid synthesis, and is a natural
inhibitor of CPT1A. CPT1A is sensitive to malonyl-CoA, and the
sensitivity depends on the concentration of malonyl-CoA (Robinson
and Zammit, 1982). However, fasting or insulin deficit significantly
reduces CPT1A’s sensitivity to malonyl-CoA (Park et al., 1995;
Akkaoui et al., 2009). CPT1A structure has a short N-terminus and a
major C-terminus containing a catalytic site and a malonyl-CoA
binding site. Malonyl-CoA inhibition of CPT1A will be lost as a
result of the specific area of the N-terminal interacting with the
FIGURE 5
Regulation of CPT1A at protein level (enzyme activity) (A) and gene expression level (B).
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malonyl-CoA binding site in the C-terminal (Morillas et al., 2004;
Lopez-Vinas et al., 2007;Rufer et al., 2009;Rao et al., 2011).
Malonyl-CoA inhibits CPT1A activity through allosteric
inhibition and in a concentration-dependent manner, and the
C-termini of CPT1A served as the malonyl-CoA binding site
(Rao et al., 2011). The affinity for malonyl-CoA can also be
influenced by the N-terminal state of CPT1A (residues 1–42),
which has two possible conformational states (Nαinhibitory state
and Nβnon-inhibitory state) (Lopez-Vinas et al., 2007;Rao et al.,
2011). The presence of a curved, amphiphilic binding surface is
necessary for the non-inhibitory state (Rao et al., 2011).
CPT1A activity can be regulated via the AMPK-ACC-CPT1A
axis (Figure 6)(Yao et al., 2020). ACC is inhibited through
phosphorylation by AMPK, and ACC’s inhibiting effect on
CPT1A is relieved by lowering the malonyl-CoA level (Yao et al.,
2020).
CPT1A in diseases
CPT1A deficiency
CPT1A deficiency is a rare mitochondrial FAO disorder caused
by autosomal recessive mutations (Bellusci et al., 2017). The CPT1A
deficiency can trigger a variety of illnesses, including hepatic
encephalopathy, recurrent hypoglycemia, hepatomegaly,
hyperammonemia, renal tubular acidosis, and so on (Collins
et al., 2010). Rapid onset, frequent recurrence, and high mortality
are significant features for CPT1A deficiency. Symptoms are
classified into three classes according to the frequency (Figure 7).
Mutations associated with CPT1A deficiency can be divided into
two categories: type one affect directly the catalytic center, which
results in loss of activity (functional determinant); type two affects
the stability of the enzyme, which indirectly decreases the catalytic
efficiency (structural determinant) (Gobin et al., 2003).
Mutations A275T, R357W, A414V, L484P, and Y498C, far away
from the active region, decrease activity by affecting the stability of
CPT1A (Gobin et al., 2003). C304W, P479L, and R395 deletion
almost lose activity (Brown et al., 2001). High mortality rate mutants
P479L is a frequent CPT1A mutation found in Arctic regions like
Canada (Rajakumar et al., 2009;Gessner et al., 2010). Additionally,
G709E and G710E, two sites essential for the hydrophobic core in
the catalytic site, can abolish CPT1A activity (Dai et al., 2000). The
hydrophobic catalytic core is altered when Gly709 or Gly710 is
changed to a Glu, which introduces a large and negatively charged
group (Gobin et al., 2003). This mutation is close to the catalytic
His473 residue and the carnitine binding site, which can
significantly change the hydrophobic pocket of CPT1A (Gobin
et al., 2003). We compiled the majority of the reported natural
mutations so far and mapped them onto CPT1A structure model
(Figure 8)(Table 1).
Currently, there is no specific drug for CPT1A deficiency, and
diet control is the main therapy. Tubular acidosis can be improved
after treatment with medium chain triglyceride in CPT1A deficiency
patients (Falik-Borenstein et al., 1992). Therefore, timely screening
and diagnosis of CPT1A defects appear to be particularly important,
and CPT1A defects can be finally confirmed based on results from
multiple aspects (Figure 7).
CPT1A and metabolic diseases
Patients with metabolic syndrome, obesity, and type 2 diabetes
frequently have non-alcoholic fatty liver disease,
hypertriglyceridemia, and other lipid metabolism abnormalities,
which can be somewhat improved by increasing CPT1A
expression (Deprince et al., 2020). Increased CPT1A expression
has been shown to drastically lower liver triglyceride levels
(Stefanovic-Racic et al., 2008), and suppress JNK factor to
prevent the inflammatory response brought on by free fatty acids
(Gao et al., 2011). Fatty acid accumulation can cause the
development of insulin resistance, which can eventually result in
type 2 diabetes and hyperinsulinemia (Levin et al., 2007; Pan et al.,
1997).
CPT1A in vascular diseases
Metabolism of endothelial cell depends on FAO to resist
oxidative stress in the development of blood vessels, and CPT1A
plays a crucial role in this process, offering a new potential target for
the treatment of vascular-related diseases (Rohlenova et al., 2018).
CPT1A in heart failure
Heart failure is one of the top causes of death and disability
around the world, but there is yet no safe and effective clinical
therapy for heart failure (Bui et al., 2011). The clinical study of the
CPT1A inhibitor etomoxir showed improvement in heart failure,
but was ended prematurely due to elevated liver transaminase in
enrolled patients (Holubarsch et al., 2007).
Perhexiline was an effective anti-angina drug used in the last
century, but was recalled by the manufacturer because of
hepatotoxicity and peripheral neurotoxicity (Ashrafian et al.,
2007). Later studies confirmed that Perhexiline could selectively
block CPT1A in liver and heart, and had an ideal inhibitory effect on
FAO and improved the oxidation of carbohydrate in the heart
(Ashrafian et al., 2007).
CPT1A in NAFLD
The global obesity epidemic has dramatically increased the
prevalence of non-alcoholic fatty liver disease (NAFLD), with no
FIGURE 6
Summary of CPT1A-related diseases.
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approved treatment now (Weber et al., 2020). Deficient CPT1A
expression in the liver results in a healthy steatotic state that protects
against high-fat diet-induced liver damage and increases adipose
browning in a PPARα-FGF21 axis dependent manner, suggesting
that inhibition of hepatic CPT1A may serve as a viable strategy for
the treatment of obesity and NAFLD (Weber et al., 2020;Sun et al.,
2021).
CPT1A in multiple sclerosis
Inuits have a low prevalence of multiple sclerosis, possibly
associated with in CPT1A P479L mutation (Morkholt et al.,
2019). This point mutation result in 22% residual activity of the
CPT1A (Collins et al., 2010). CPT1A inhibition may represent a
prospective therapeutic therapy for multiple sclerosis.
CPT1A in renal fibrosis
Renal fibrosis is a result of several types of chronic kidney
diseases, and currently, the only treatment is to control blood
pressure and blood sugar levels (Drawz and Rosenberg, 2013).
With conditional overexpression of CPT1A, mitochondrial
dysfunction in the fibrosis kidney can be alleviated, and renal
fibrosis can be significantly decreased (Miguel et al., 2021). Gain
of function in CPT1A strategy may be a novel approach to treating
fibrosis in renal fibrosis (Miguel et al., 2021).
CPT1A and cancer
Oxidative stress is the key element that causes prostate cancer to
develop (Khandrika et al., 2009). Androgens may raise the levels of
CPT1A and the accumulation of reactive oxygen species, which are
closely linked to prostate cancer cell proliferation and differentiation
(Joshi et al., 2020). Currently, the primary treatments for prostate
cancer include diet modification and the use of antioxidants, while
CPT1A inhibition may provide novel therapeutic options (Lin et al.,
2010).
One characteristic of cancer is metabolic reprogramming, which
provides tumor cells the basic elements for fast cell growth and
maintains cell survival under hypoxic or nutrient-deficient
conditions (Yoshida, 2015). Abnormal fat metabolism has a
profound impact on cell carcinogenesis. As an important source
of NADH, NADPH, FADH2 and ATP, FAO plays a key role in
various stages of tumor occurrence, development and metastasis
(Wang et al., 2021). CPT1A is the critical rate-limiting enzyme in
FAO, responsible for transporting fatty acids from cytoplasm to
mitochondria for oxidation. There is evidence that CPT1A is crucial
for metabolic adaptability in the development of cancer, and CPT1A
inhibition slows the spread of cancer (Tang et al., 2022).
FIGURE 7
On the left are the symptoms of CPT1A deficiency gathered from Genetic and Rare Diseases (GARD) Information Center (https://rarediseases.info.
nih.gov/). On the right is the confirmatory screening process for CPT1A deficiency diagnosis. The normal value of the C0/(C16 +C18) ratio is 278.75; Total
carnitine is normal at 33–70 mmol/L and free carnitine is normal at 28–52 mmol/L (Dowsett et al., 2017).
FIGURE 8
CPT1A deficiency related mutations reported in patients. (A) The
CPT1A structure (from AlphaFold database) is colored by grey. The Cα
atoms of the CPT1A mutations in patients are shown as red spheres.
R123C, C304W, T314I, R316G, F343V, R357W, E360G, R395
(missing), A414V, D454G, G465W, P479L, L484P, Y498C, G709E, and
G710E are among the missense mutations discovered in CPT1A.
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According to growing amounts of experimental evidence
published in reputable journals in recent years, CPT1A may be
a significant drug target for a number of cancer cells, including
breast cancer (Xiong et al., 2018;Tan et al., 2021), prostate cancer
(Schlaepfer et al., 2014;Joshi et al., 2019), glioblastoma (Jiang et al.,
2022;Kim et al., 2022;Luo et al., 2022), colon cancer (Wang et al.,
2018), gastric cancer (Wang et al., 2019;Wang et al., 2020),
multiple myeloma (Shi et al., 2016), nasopharyngeal cancer
(Tan et al., 2018;Tang et al., 2022), etc. CPT1 plays an
important role in the occurrence and development for these
cancers, and pharmacological inhibition of CPT1A can
effectively inhibit cancer cell proliferation, which makes CPT1 a
possible molecular marker for tumor diagnosis and a new target for
anti-tumor therapy.
CPT1A in breast cancer
Breast cancer is the most prevalent and leading cause of cancer
death among women globally, which has a poor prognosis, a high
rate of recurrence and metastasis, and a high fatality rate (Waks and
Winer, 2019). In 2020, there were 2.26 million new instances of
breast cancer worldwide, overtaking lung cancer (2.21 million) for
the first time to take the top place among all cancers, according to
the International Agency for Research on Cancer’s (IARC) estimate
of the global cancer (Ferlay et al., 2021).
Invasion and lymphangiogenesis in breast cancer cells can be
inhibited by CPT1A knockdown, and CPT1A-null Human Dermal
Lymphatic Endothelial Cells (HDLEC cells) consistently showed
impaired invasion and lymphangiogenesis (Xiong et al., 2018).
CPT1A knockdown reduced the expression of lymphangiogenic
markers like Vascular endothelial growth factor receptor-3
(VEGFR-3) in HDLEC cells via acetyl-CoA-mediated Histone
H3 lysine 9 acetylation (H3K9ac), which can be reversed by the
addition of acetate (Xiong et al., 2018).
Myc-overexpressing triple-negative breast cancer (TNBC) has a
greater bioenergetic dependence on FAO, and CPT1A can be
pharmaceutically inhibited to reduce energy metabolism in Myc-
overexpressing TNBC cells and stop tumor growth in a xenograft
model of Myc-overexpressing TNBC (Camarda et al., 2016;Park et al.,
2016). This suggests that CPT1A inhibition may be a promising
therapeutic approach for this particular subtype of breast cancer.
Besides, Chemotherapy (CT) and radiotherapy (RT) target
rapidly dividing cells but still have significant normal tissue
toxicity. One indicator of RT and CT resistant tumor cells is
thought to be the abnormal upregulation of CPT1A-dependent
FAO (Corn et al., 2020). High CPT1A expression, increased
FAO, and a poor prognosis are characteristics of radiation-
resistant breast cancer cells (Corn et al., 2020). Radiation
resistant breast cancer cells respond to ionizing radiation by
increasing FAO and ATP production, resulting in increased
phosphorylation of extracellular signal regulated kinase 1/2
(ERK1/2), decreased apoptosis, and promotes a more aggressive
phenotype (Han et al., 2019). Drug candidates such as Etomoxir or
its analogs, which inhibits CPT1A and FAO, can be developed as RT
and CT sensitizers in breast cancer (Han et al., 2019).
CPT1A in prostate cancer
The incidence of prostate cancer ranks the second among male
malignant tumors in the world (Schlaepfer et al., 2014). In
United States, prostate cancer has surpassed lung cancer,
becoming the most serious malignant tumor (Carlsson et al.,
2012). China has lower rates of prostate cancer than Western
nations, but these rates have been rising recently (Culp et al., 2020).
TABLE 1 Natural mutations of CPT1A found in patients.
Gene Protein Disease Description Effect References
c.367C>T R123C CPT1A deficiency —Brown et al. (2001)
c.912C>T/c.912C>G C304W CPT1A deficiency decreased stability Brown et al. (2001)
c.941C>T T314I CPT1A deficiency —Stoler et al. (2004)
c.946C>G R316G CPT1A deficiency —Bennett et al. (2004)
c.1027T>G F343V CPT1A deficiency —Bennett et al. (2004)
c.1069C>T R357W CPT1A deficiency decreased stability Brown et al. (2001)
c.1079A>G E360G CPT1A deficiency reduced protein levels Ogawa et al. (2002)
—R395 (missing) CPT1A deficiency loss of activity Brown et al. (2001)
c.1241C>T A414V CPT1A deficiency decreased activity Gobin et al. (2002), Gobin et al. (2003)
c.1361A>G D454G CPT1A deficiency loss of activity IJlst et al. (1998)
c.1393G>T G465W CPT1A deficiency —Bennett et al. (2004)
c.1436C>T P479L CPT1A deficiency decreased activity Brown et al. (2001)
c.1451T>C L484P CPT1A deficiency decreased stability Brown et al. (2001)
c.1493A>G Y498C CPT1A deficiency decreased activity Gobin et al. (2002), Gobin et al. (2003)
c.2126G>A G709E CPT1A deficiency loss of activity Gobin et al. (2003)
c.2129G>A G710E CPT1A deficiency loss of activity Prip-Buus et al. (2001), Gobin et al. (2003)
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Rather than using aerobic glycolysis, prostate cancer prefers
lipid for fuel. Prostate cancer cells may have less vitality after therapy
with etomoxir, irreversible inhibitor of CPT1A, and etomoxir
treatment in mice reduced xenograft growth for a period of
21 days (Schlaepfer et al., 2014). Reduced mTOR signaling,
elevated caspase-3 activation, and decreased androgen receptor
expression are linked to these outcomes (Schlaepfer et al., 2014).
The growth of prostate cancer may be aided by a stress state caused
by reactive oxygen species (ROS) that is linked to CPT1A
overexpression (Joshi et al., 2020). Besides, increased histone
acetylation has been observed in prostate cancer cells that over-
express CPT1A, suggesting that acetylation may be a means by
which CPT1A controls prostate cancer cell proliferation (Joshi et al.,
2019). These facts highlight the therapeutic potential of CPT1A
blockade to prevent prostate cancer.
CPT1A in lung cancer
Lung cancer is one of the most common malignant tumors in
humans, and its incidence and mortality are increasing year by year
worldwide (de Sousa and Carvalho, 2018). Cisplatin is one widely
used chemotherapy drugs for lung cancer (O’Byrne et al., 2011;
Wang and Lippard, 2005). Knockdown of CPT1A can promote
tumor cell susceptibility to Cisplatin. The CPT1A inhibitor etomoxir
can affect and coordinate with the conventional chemotherapy drug
cisplatin to increase tumor cell sensitivity to the chemotherapeutic
agent, inhibit tumor cell proliferation and promote apoptosis, thus
providing a novel approach to improving the efficacy of
chemotherapy in non-small cell lung cancer (Dheeraj et al., 2018;
Hoy et al., 2021).
CPT1A in glioblastoma multiforme (GBM)
GBM is the most common and difficult central nervous system
malignancies, with a 5-year survival rate of 6.8% (Ostrom et al.,
2020). Radiotherapy is the primary treatment for GBM, and
radiotherapy plus immunotherapy is emerging as a new option
due to the strong resistance and poor efficacy of GBM to
radiotherapy (Arina et al., 2020). However, tumor cells after
radiotherapy develop a tolerance to immunotherapy, allowing
tumor cells to escape the killing of immune cells, leading to
treatment failure (Darragh et al., 2018). After treatment of radio-
resistant GBM cells with the CPT1A inhibitor etomoxir, Oxygen
Consumption Rate (OCR) and ATP production were significantly
inhibited, suggesting that energy conversion from glycolysis to FAO
occurs in radio-resistant GBM cells (Jiang et al., 2022). CPT1A and
CD47 are highly expressed in radiotherapy resistant GBM tumors,
and inhibition of CPT1A can result in decreased CD47 expression
and increased macrophage phagocytosis of tumor cells (Jiang et al.,
2022). High expression of CPT1A not only enhances radiotherapy
resistance in GBM tumor cells, but also enhances immune escape of
macrophages through CD47, suggesting CPT1A as a novel strategy
for the treatment of recurrent GBM multiforme.
CPT1A in colon cancer
Colon cancer develops in adipose-rich microenvironment, and
CPT1A overexpression is crucial for adipocytes to promote tumor
growth in colon cancer (Wen et al., 2017;Pearce et al., 2018). CPT1A
upregulation is a key metabolic alteration that cancer cells use to
promote β-catenin acetylation and activation, while knockdown of
CPT1A can reduce the expression of genes linked with colon cancer
cells downstream of Wnt/β-catenin (Wen et al., 2017). Overall,
CPT1A inhibition may be a useful strategy to lessen the promotion
impact of adipocytes on colon cancer.
CPT1A in gastric cancer
Gastric cancer is a malignancy of stomach lining (Torre et al.,
2015;Sung et al., 2021). In gastric cancer, the calcium-binding
cytosolic protein S100A10 is overexpressed and is essential for the
invasion and migration of tumor cells (El-Rifai et al., 2002).
CPT1A succinylated S100A10 at lysine 47, and the degree of
succinylation was elevated in human gastric cancer (Wang
et al., 2019). In summary, S100A10 succinylation promotes
gastric cancer progression and is regulated by CPT1A-mediated
succinylation and sirtuin5 (SIRT5)-mediated desuccinylation
(Wang et al., 2019).
CPT1A in ovarian cancer
CPT1A was found to be highly expressed in ovarian cancer, and
its overexpression is linked to a poor survival in ovarian cancer
patients (Shao et al., 2016;Tan et al., 2018). CPT1A inactivation
reduced cellular ATP levels and caused cell cycle arrest at G0/
G1 stage, implying that ovarian cancer cells rely on CPT1A-
mediated FAO for cell cycle progression (Shao et al., 2016).
CPT1A in nasopharyngeal carcinoma
Nasopharyngeal carcinoma (NPC) incidence can be affected by
genetic susceptibility, and environmental factors. In NPC cells,
CPT1A was the only up-expressed carnitine palmitoyl transferase
(Tang et al., 2022). Upregulated CPT1A enhances the production of
nucleoside metabolic intermediates that promote cell cycle
progression is increased in NPC cells (Tang et al., 2022). Belgian
scientists revealed via isotope labeling that palmitate-derived
carbons considerably augmented the Krebs cycle and could be
integrated into nucleotide precursors such as aspartic acid, and
pyrimidine nucleoside triphosphate (Schoors et al., 2015). Inhibiting
CPT1A causes cells to deplete stored aspartic acid and dNTP,
impairs de novo dNTP synthesis, and inhibits NPC cell cycle’s
DNA replication at G1/S transition, implying a potential
treatment strategy for NPC based on lipid metabolism regulation
(Schoors et al., 2015;Tan et al., 2018).
Furthermore, radiation resistance is still a significant barrier for
NPC treatment (Chua et al., 2016;Tan et al., 2018). NPC radiation
resistance may be enhanced via the PPAR coactivator-1α(PGC1α)/
CCAAT/enhancer binding protein β(CEBPB)/CPT1A/FAO
signaling axis (Du et al., 2019). Radiation-resistant NPC cells
consistently displayed active up-regulation of CPT1A, and
inhibition of CPT1A could render NPC cells once again
vulnerable to radiation treatment by inducing mitochondrial
apoptosis (Tan et al., 2018).
CPT1A in leukemia
In acute myeloid leukemia (AML), overexpression of CPT1A
indicates poor clinical prognosis, and strong synergistic inhibitory
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effects on AML were seen when the CPT1A-selective inhibitor
ST1326 and the Bcl-2 inhibitor ABT199 were applied in
combination (Mao et al., 2021). Overall, CPT1A expression is
abnormally high in AML, and targeted suppression of CPT1A
has potent anti-leukemic effects, suggesting that CPT1A might be
a therapeutic target for the treatment of AML (Mao et al., 2021).
CPT1A as a target for cancer treatment
CPT1A inhibitors can lessen the survivability of cancer cells, so
CPT1A may be a useful target for cancer therapy. The main
drawback of CPT1A blockage is the undesirable impact on non-
tumor cells given the extensive tissue distribution of CPT1A.
Unfortunately, there has not yet been any evidence of apparent
selectivity against other CPT1 isoforms when developing small
molecules as CPT1A inhibitors.
CPT1A and drug development
CPT1A is an intriguing target with significant potential for
pharmacological application. For decades, drugs targeting CPT1A
have been the focus of research on diseases like type 2 diabetes
(T2D), obesity, and other disorders (Rufer et al., 2009). Therefore,
drug development targeting CPT1A has attracted much attention.
CPT1A inhibitors
The efforts to study the molecular mechanisms of CPT1A
inhibition in disease intervention have increased in recent years due
to the association with cancer (Schlaepfer et al., 2014). However, there
are few small-molecule inhibitors of CPT1A. In the past, efforts were
concentrated on CPT1A inhibitors, primarily two main kinds of
inhibitors including substrate derivatives, glycidic acid derivatives,
and malonyl-CoA analogues (Figure 9)(Ceccarelli et al., 2011).
Etomoxir and 2-tetradecylglycidic acid (TDGA) are both
ethylene oxide compounds. Etomoxir and TDGA can bind to the
active site of CPT1A to produce inhibitory effects (Brady and Brady,
1986;Ratheiser et al., 1991). These two inhibitors belong to the first
developed class. However, Etomoxir lacks selectivity to
CPT1 isoforms, and TDGA can affect the renin angiotensin
system, resulting in myocardial hypertrophy and other side
effects (Brady and Brady, 1986). Etomoxir is a strong irreversible
inhibitor of CPT1A (Selby and Sherratt, 1989). However, preclinical
research was stopped because of hepatotoxicity after a phase II
clinical trial (Holubarsch et al., 2007).
An amino-carnitine analog called ST1326 (oral formulation-
Teglicar) was initially created for diabetic ketoacidosis (Giannessi
et al., 2003). ST1326 belongs to formyl-carnitine derivatives, which
has a specific and reversible inhibitory effect on liver CPT1A, and is
currently used as a novel anti-hyperglycemic drug (Conti et al.,
2011). Compared to etomoxir, ST1326 (oral formulation-Teglicar) is
more selective for CPT1A while CPT1B can also be inhibited by
etomoxir (Conti et al., 2011). ST1326 can significantly improve
hyperglycemia and adjust the dynamic balance of glucose in obesity
and type 2 diabetes models, showing good application prospects
(Conti et al., 2011).
It was discovered that C75 directly stimulated CPT1A activity
(Idrovo et al., 2012). However, it was also found that CPT1A is
inhibited by low amounts of C75 that have been converted to C75-
CoA (Mera et al., 2009). There is still debate about this matter,
though.
Perhexiline, a clinical CPT1A/CPT2 inhibitor, is approved for
the management of angina pectoris outside of the United States
(Ashrafian et al., 2007). Perhexiline increases the efficiency of
oxygen consumption by blocking FAO and switching the energy
metabolism from lipid to carbohydrate. Despite being effective for
angina pectoris, perhexiline was reported with neurotoxicity and
hepatotoxicity for prolonged use (Ren et al., 2020).
CPT1A is a significant therapeutic target due to its important
function in a variety of illnesses (Schlaepfer and Joshi, 2020).
CPT1A’s protein structure is still unknown, though. It is crucial
to discover the structure and catalytic role of the enzyme in order to
design more powerful inhibitors. To avoid side effects, selectivity
needs to be considered further. For instance, the fact that perhexiline
targets both CPT1A and CPT2 raises the possibility that the negative
effects may be related to its lack of isoform selectivity.
The isoform selectivity of CPT1A inhibitor has a significant
impact on how the therapeutic benefit is evaluated. The best-studied
CPT1 inhibitor, etomoxir, may have the problem of off-target side
effect (Yao et al., 2018). When assessing safety, liver selectivity
should also be taken into account for CPT1A.
CPT1A agonists
Moderately increasing the expression or activity of CPT1A can
promote FAO and improve a variety of metabolic diseases caused by
high fat diet (Figure 10).
C75 and baicalin can directly activate CPT1A (Idrovo et al.,
2012;Fang et al., 2020). In addition, several small molecules can
indirectly activate CPT1A by acting on ACC2, including the AMPK
activators metformin and AICAR (Tomita et al., 2005), and the
ACC2 inhibitors TOFA and Soraphen (Agostini et al., 2022). Anti-
Sense Oligonucleotide (ASO)-mediated inhibition of ACC2 may
also play a role in activating CPT1A. CPT1A can also be indirectly
promoted by PPAR activators Fibrates and GW501516 (Cox, 2017).
However, overexpression of CPT1A may increase the FAO rate,
promote cell metabolism, and accelerate cell apoptosis, which brings
certain difficulties for the development of related drugs.
FIGURE 9
Four well-studied inhibitors (Etomoxir, Perhexiline, ST1326,
TDGA) of CPT1A.
Frontiers in Pharmacology frontiersin.org10
Liang 10.3389/fphar.2023.1160440

Conclusion and perspectives
In summary, as a key enzyme in FAO, CPT1A affects the
occurrence and development of a variety of diseases. The
physiological function and impact of CPT1A are becoming
increasingly better understood, which has important guiding
significance for the research of CPT1A related diseases, and
also provides support for the drug development and application
based on targeting CPT1A. CPT1A has become a focus of
pharmaceutical research due to CPT1A pathogenic mutations
and abnormal expression in malignancies. Interest in CPT1A’s
role in cancer has increased recently. The mechanisms
through which CPT1A aids in cancer cell survival remain not
fully clarified. Given that CPT1A was reported to promote
anoikis-resistance and metastasis in cancers like colorectal cancer,
CPT1A would be a desirable target to counteract resistance of
anticancer drugs (Wang et al., 2018). Although currently
available small-molecule drugs targeting CPT1A have shown
promising therapeutic effects, their off-target effects and
side effects are still the biggest obstacles to their application.
Finally, further research on the structure of CPT1A will
continue to improve the specificity of drug selectivity to
CPT1A to avoid off-target effect and other undesired side effects,
which will provide safer and more effective drugs for the clinical
therapy.
Author contributions
KL wrote the manuscript, made the figures, and approved the
final manuscript.
Funding
This work is financially supported by the Boya Postdoctoral program.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
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