COENZYME Q10 AFFECTS EXPRESSION OF GENES INVOLVED IN CELL SIGNALLING, METABOLISM AND TRANSPORT IN HUMAN CACO-2 CELLS
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The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218
Coenzyme Q10 affects expression of genes involved in cell
signalling, metabolism and transport in human CaCo-2 cells
David A. Groneberga , Birgit Kindermannb , Martin Althammerb , Maja Klapperc ,
Jürgen Vormannd , Gian P. Littarrue , Frank Döringc,∗
a Biomedical Research Institute, Otto-Heubner-Centre, Charité School of Medicine, Free University and Humboldt-University,
D-13353 Berlin, Germany
b Institute of Nutritional Sciences, Molecular Nutrition Unit, Technical University of Munich, D-85350 Freising-Weihenstephan, Germany
c Research Group Molecular Nutrition Unit, University of Kiel, c/o Bundesanstalt für Ernährung und Lebensmittel,
Hermann-Weigmann-Straße 1, 24105 Kiel, Germany
d Institute for Prevention and Nutrition, 85737 Ismaning, Germany
e Istituto di Biochimica, Università Politecnica delle Marche, Via Ranieri, 60131 Ancona, Italy
Received 19 October 2004; received in revised form 22 November 2004; accepted 25 November 2004
Abstract
Coenzyme Q10 is an essential cofactor in the electron transport chain and serves as an important antioxidant in both mitochon-
dria and lipid membranes. CoQ10 is also an obligatory cofactor for the function of uncoupling proteins. Furthermore, dietary
supplementation affecting CoQ10 levels has been shown in a number of organisms to cause multiple phenotypic effects. However,
the molecular mechanisms to explain pleiotrophic effects of CoQ10 are not clear yet and it is likely that CoQ10 targets the expres-
sion of multiple genes. We therefore utilized gene expression profiling based on human oligonucleotide sequences to examine
the expression in the human intestinal cell line CaCo-2 in relation to CoQ10 treatment. CoQ10 caused an increased expression of
694 genes at threshold-factor of 2.0 or more. Only one gene was down-regulated 1.5–2-fold. Real-time RT-PCR confirmed the
differential expression for seven selected target genes. The identified genes encode proteins involved in cell signalling (n = 79),
intermediary metabolism (n = 58), transport (n = 47), transcription control (n = 32), disease mutation (n = 24), phosphorylation
(n = 19), embryonal development (n = 13) and binding (n = 9). In conclusion, these findings indicate a prominent role of CoQ10
as a potent gene regulator. The presently identified comprehensive list of genes regulated by CoQ10 may be used for further
studies to identify the molecular mechanism of CoQ10 on gene expression.
© 2004 Elsevier Ltd. All rights reserved.
Keywords: Coenzyme Q10 ; Gene expression; Microarray; Real-time PCR; Dietary supplementation
1. Introduction
Abbreviations: CoQ10 , coenzyme Q10
∗ Corresponding author. Tel.: +49 431 6092472;
Coenzyme Q, which is also known as ubiquinone,
fax: +49 431 60971.
is a lipid-soluble molecule composed of a redox active
E-mail address: doering@email.uni-kiel.de (F. Döring).
1357-2725/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biocel.2004.11.017D.A. Groneberg et al. / The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218 1209
quinoid moiety and a hydrophobic tail. The predom- Baik & Beal, 1998). Years before CoQ10 became avail-
inant form of coenzyme Q in humans is coenzyme able for oral supplementation a lifespan prolonging
Q10 , which contains 10 isoprenoid units in the tail. effect had been found when coenzyme Q7 was ad-
Coenzyme Q is soluble and mobile in the hydropho- ministered to a mouse model of muscular dystrophy
bic core of the phospholipid bilayer of the inner mem- (Scholler, Jones, Littarru & Folkers, 1970). Recently
brane of the mitochondria and is an essential cofactor in coenzyme Q supplementation was found to protect
the electron transport chain where it accepts electrons from age-related DNA double-strand breaks and to in-
from complexes I and II (Beyer, 1992; Do, Schultz & crease lifespan in rats with a PUFA-rich diet (Quiles,
Clarke, 1996; Ernster & Dallner, 1995). CoQ10 also Ochoa, Huertas & Mataix, 2004). In humans, it has
serves as a potent antioxidant in mitochondria and been suggested that CoQ10 improves exercise per-
lipid membranes (Forsmark-Andree, Lee, Dallner & formance (Laaksonen, Fogelholm, Himberg, Laakso
Ernster, 1997; Noack, Kube & Augustin, 1994). It ef- & Salorinne, 1995). In different cardiovascular dis-
ficiently protects membrane phospholipids from per- eases, including cardiomyopathy, relatively low levels
oxidation and also mitochondrial DNA and membrane of CoQ10 in myocardial tissue have been reported. Posi-
proteins from free-radical-induced oxidative damage. tive clinical and haemodynamic effects of oral CoQ10 -
This protective role of CoQ10 is independent of the ef- supplementation have been observed in double-blind
fect of exogenous antioxidants, such as Vitamin E, and trials, especially in chronic heart failure (Overvad et al.,
it can both prevent the formation of free lipid radicals 1999).
and eliminate them either directly or by regenerating Interest in CoQ10 has increased during recent years,
Vitamin E (Pobezhimova & Voinikov, 2000). In the mainly because of its antioxidant function and its di-
last decade the antioxidant role of CoQ10 in plasma etary supplement. Whereas the molecular mechanism
lipoproteins has been deeply investigated (Alleva et of CoQ10 -mediated antioxidant function is partially re-
al., 1995; Thomas, Witting & Stocker, 1999). Fur- solved, exact mechanisms explaining multiple effects
thermore, dihydroorotate dehydrogenase, the fourth of CoQ10 have not been elucidated so far. By contrast,
enzyme of pyrimidine synthesis, needs CoQ10 for it has been shown recently, that classical antioxidants
activity. In addition, CoQ10 is an obligatory cofac- such as Vitamin E or polyphenols affect specific genes
tor for the function of uncoupling proteins UCP1- independently of their antioxidant/radical-scavenging
3 (Echtay, Winkler & Klingenberg, 2000; Echtay, activity (Okabe, Fujimoto, Sueoka, Suganuma &
Winkler, Frischmuth & Klingenberg, 2001). More re- Fujiki, 2001; Rimbach et al., 2002). Therefore, we hy-
cently, it has been shown, that CoQ10 is necessary pothesize that the antioxidant CoQ10 may also influ-
for mouse embryonic development (Levavasseur et al., ence gene expression.
2001).
Based on its biochemical role and some postu-
lated functions, CoQ10 can/may be used in a va- 2. Material and methods
riety of physiological and clinical conditions, as a
nutritional supplement (Overvad et al., 1999) but fur- 2.1. Cell culture
ther clinical studies are needed to document useful-
ness of this compound in clinical practice. As shown CaCo-2 cells as gastrointestinal cell type were cho-
in the model organism Caenorhabditis elegans, a di- sen and provided by American Type Culture Collection
etary source of CoQ10 is essential for growth of long- (ATCC, Rockville, MD) and were used between pas-
lived animals (Jonassen, Larsen & Clarke, 2001). Even sage 70 and 110. Cells were cultured and passaged in
though several studies did not show an effect of of MEM-alpha supplemented with 10% fetal calf serum
CoQ10 -supplementation on the lifespan of rats and (FCS), 2 mM glutamine, 1% MEM non essential amino
mice (Lonnrot, Metsa-Ketela & Alho, 1995; Lonnrot, acids, 10,000 g/ml Pen-Strep and 250 g/ml Fungi-
Holm, Lagerstedt, Huhtala & Alho, 1998) a signifi- zone (all from Invitrogen) in a humidified incubator at
cant increase in survivial was found, upon CoQ10 treat- 37 ◦ C under an atmosphere of 5% CO2 . Cells were pas-
ment, in a transgenic animal model of familial amy- saged at preconfluent densities by the use of a solution
otrophic lateral sclerosis (Matthews, Yang, Browne, containing 0.05% trypsin and 5 mM EDTA.1210 D.A. Groneberg et al. / The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218
2.2. CoQ10 -treatment mogenate was centrifugated at 15,000 rpm at 4 ◦ C
for 30 min and the cytosolic supernatant was incu-
A liposomal CoQ10 preparation, obtained from Dr. bated with the fluorogenic caspase-3 tetrapeptide-
Enzmann (MSE Pharmazeutika, Bad Homburg, Ger- substrate Ac-DEVD-AMC (Calbiochem, Bad Soden,
many), was used for CoQ10 treament. Control cells Germany) at a final concentration of 20 M. Cleav-
lipo age of the caspase-3 substrate was followed by de-
were treated with the same amount of liposomes (Q10 ).
termination of emission at 460 nm after excitation at
390 nm using a fluorescence multiwell-plate reader
2.3. Proliferation and cell integrity
(Fluoroskan Ascent, Labsystems, Bornheim-Hersel,
Germany).
CaCo-2-cells were seeded onto 24-well plates and
were grown for 72 h in medium. Cells were exposed for
24 h (cell integrity) or 72 h (proliferation) to medium 2.4.2. DNA fragmentation
alone (control) or medium containing CoQ10 in con- Nuclear fragmentation as a late marker of apopto-
centrations of 25, 50, 150 and 250 M. Cell counts sis was determined for the concentrations 250, 150,
for cell integrity and proliferation were done using 50 and 25 M by staining of DNA with Hoechst
SYTOX-Green (Bioprobes, Leiden, The Netherlands), 33258 (Sigma). Cells (3 × 104 ) were incubated with
which becomes fluorescent after DNA binding. There- the test compounds for the times indicated and there-
fore, cells were incubated with SYTOX-Green to deter- after washed with PBS, allowed to air-dry for 30 min,
mine the number of cells with impaired integrity based fixed with 2% paraformaldehyde and finally stained
on a calibration curve. Afterwards cells were lysed by with 1 g/ml Hoechst 33258. Visualization was done
6% Triton X-100 in isotonic NaCl and total cell num- under the inverted fluorescence microscope.
bers were determined. The percentage of cells with
impaired integrity was determined by assessing per- 2.5. MWG pan human 10 k array
meability for SYTOX-Green.
Oligonucleotide arrays on glass slides containing
2.4. Detection of apoptosis 9850 gene specific oligonucleotide probes (50 mer)
were obtained from MWG Biotech AG (Ebersberg,
To identify potential deleterious effects arising from Germany). RNA preparation, reverse transcription, la-
CoQ10 treatment, apoptosis markers such as caspase- beling and hybridization were performed according to
3 and DNA fragmentation were assessed as described the recommendations of the manufacturer. Total RNA
previously (Wenzel & Daniel, 2004) using the follow- from either control or CoQ10 -treated cells from three
ing protocols. independent experiments was pooled and reverse tran-
scription in the presence of either Cy3- or Cy5-labeled
2.4.1. Caspase-3 dCTP (Amersham Bioscience Europe, Freiburg, Ger-
Caspase-3 was determined as apoptosis marker. many) was performed to produce fluorescence labeled
Colonocytes were seeded at a density of 5 × 105 first-strand cDNAs. Arrays were scanned (Affymetrix
per well onto 6-well plates (Renner, Darmstadt, Ger- 428TM Array Scanner, Santa Clara, CA, USA) un-
many) and allowed to adhere for 24 h. Cells were der dried conditions. The obtained data were nor-
then exposed for the times indicated to the test com- malized and analyzed by using ImaGeneTM 4.2 soft-
pounds. Subsequently, cells were trypsinized, cell ware (BioDiscovery Inc., Los Angeles, CA, USA).
count was performed and then the cells were cen- Three hybridizations (microarrays) were carried out
trifuged at 2500 rpm for 10 min. Cytosolic extracts in three independent experiments. Genes were consid-
were prepared by adding 750 l of a buffer containing ered as up- or down-regulated if the change was 2-
2 mM EDTA, 0.1% CHAPS, 5 mM DTT, 1 mM PMSF, fold or greater in at least two hybridizations. In most
10 g/ml pepstatin A, 20 g/ml leupeptin, 10 g/ml cases real-time RT-PCR showed similar or even greater
aprotinin and 10 mM HEPES/KOH, pH 7.4 to each changes in expression levels than those observed on
pellet and homogenizing by five strokes. The ho- microarrays.D.A. Groneberg et al. / The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218 1211
2.6. LightCycler real-time RT-PCR considered statistically significant at a P-value 2-fold) in the mRNA-levels were
detected for 694. No genes were down-regulated >2-
Calculations were done using the software Prism fold. Only one gene (n = 1) was down-regulated 1.5–2-
3.03 (GraphPad Software, Los Angeles, CA, USA). fold. A complete list of all regulated genes is pre-
Results for cytotoxicity, proliferation and cell integrity sented as a supplemental file on the web site of the
were analyzed using unpaired Student’s t-test and were journal. The genes can be classified into eight groups1212 D.A. Groneberg et al. / The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218 Fig. 1. Dose-dependence of the effect of coenzyme Q10 on cell in- tegrity, proliferation and caspase-3-like activity. (A) Cell integrity was measured after 24 h of incubation with medium alone (control) or containing coenzyme Q10 at various concentrations, and a count of
D.A. Groneberg et al. / The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218 1213
tions (Laaksonen et al., 1995). In contrast to the recent
characterization of molecular gene-interactions of clas-
sical antioxidants such as tocopherol or polyphenols
(Rimbach et al., 2002; Weinreb, Mandel & Youdim,
2003), the precise molecular mechanisms of CoQ10
gene-interaction have not been dissected on the cellu-
lar level in vitro so far. The present study was therefore
performed using the well characterized human CaCo-
2-cell line and gene array technology in combination
Fig. 3. Unspecific gene regulation was exluded by real-time PCR with post array analysis and a total amount of 694 reg-
experiments with the two house keeping genes GAPDH and beta-
actin. Crossing point determination by the second derivative maxi-
ulated genes was identified.
mum method. To identify CoQ10 -sensitive genes in human cells we
used CaCo-2 cells as target cells since this cell line dis-
alterations in mRNA-levels were confirmed for seven plays a common model for absorptive intestinal cells.
genes in the same direction by quantitative RT-PCR In view of the oral administration of CoQ10 , intestinal
(Table 1). cells represented here by the presently used CaCo-2
cells, are the first cells of the mammalian organisms that
are confronted by CoQ10 . Also, all of the orally given
4. Discussion CoQ10 has to pass through the intestinal epithelium and
therefore, the presently chosen in vitro cell model mim-
CoQ10 is used as nutritional supplement and has ics the first event of CoQ10 -supplementation in vivo.
been postulated to positively influence many cellular Also, absorptive intestinal cells such as CaCo-2 cells
functions(Overvad et al., 1999). As shown in the model are in contact with the high concentrations of CoQ10
organism C. elegans, a dietary source of CoQ10 is es- observed in the human body and therefore enterocytes
sential for growth of long-lived animals (Jonassen et represent an important cell type when analysing the ef-
al., 2001). Differing results were obtained regarding fects of CoQ10 . In comparison to complex tissues ob-
the lifespan of rats or mice (Lonnrot et al., 1995, 1998). tained from CoQ10 -supplemented animals or humans,
In humans, it has been suggested that CoQ10 improves our approach uses a homogenous cell population that
exercise performance and many other biological func- can be used under standardized conditions to define
Table 1
Changes in mRNA expression levels of selected genes in response to coenzyme Q10 -supplementation in CaCo-2 cells assessed by real-time
PCRa
Geneb Encoded proteinc Functiond Fold changee
Array RT-PCR
NM002934 Ribonuclease, rnase a family, 2 Signalling +16.0 ± 0.1 +18.0 ± 3.3
NM001845 Alpha 1 type IV collagen preproprotein Signalling +5.6 ± 0.3 +8.4 ± 0.3
NM024885 Tata box binding protein-associated factor Transcription +5.9 ± 0.1 +5.6 ± 0.6
XM030144 H4 histone family, member g DNA-binding −1.6 ± 0.1 −6.4 ± 2.2
NM021255 Pellino homolog 2 DNA-binding +7.4 ± 0.1 +10.7 ± 0.0
NM014547 Tropomodulin 3 Actin-binding +5.5 ± 0.2 +7.0 ± 3.2
NM000270 Purine nucleoside phosphorylase Nucleotide metabolism +3.9 ± 0.1 +11.9 ± 3.9
NM004500 Heterogeneous nuclear ribonucleoprotein C RNA-binding −1.4 ± 0.1 −0.8 ± 1.8
a List of selected Q10-sensitive genes with increased (+) or decreased (−) expression levels. Genes were originally identified by array analysis
and were confirmed by quantitative RT-PCR.
b GenBank accession number.
c Name of encoded protein.
d Proposed function of the protein.
e Magnitude of changes observed by array analysis and RT-PCR, respectively. Values are means ± S.D., n = 3.1214 D.A. Groneberg et al. / The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218
Fig. 4. Functional classification of genes with altered expression levels in response to coenzyme Q10 -supplementation in human CaCo-2 cells.
(A) Scatter plots of array data. Average intensities (log) with (x-axis) or without (y-axis) Q10 -supplemenation for each gene were plotted for three
experiments. The line of identity is shown in the middle. Dots which are significant depart from the middle line indicate genes identified in (B). The
gene functions were taken from the web-based programs of the National Center for Biotechnology Information (NCBI) at www.ncbi.nlm.nih.gov.
We refered to the reference sequences (RefSeq) which are reviewed or validated.
CoQ10 -dependent gene expression control on a cellu- apoptosis markers. CoQ10 did not have effects on the
lar level. late apoptosis phase as assessed by DNA fragmentation
Prior to the performance of gene arrays, an optimal assays. In the early phase, CoQ10 in a concentration of
non-toxic CoQ10 dosage for the CaCo-2 cells had to be 50 M led to a reduction of caspase-3 substrate activity
defined. To identify this concentration, the effects of of 50% whereas higher concentrations led to a linear in-
CoQ10 on the cellular integrity was assessed by the use crease of its activity. The test compound camptothecin
of cytotoxicity and proliferation assays. A concentra- led to a 4-fold increase of acitivity as previously re-
tion of up to 50 M did not lead to any toxicity whereas ported (Wenzel & Daniel, 2004; Wenzel, Nickel, Kuntz
a linear increasing toxicity was found up to a concen- & Daniel, 2004). Therefore, an optimal concentration
tration of 150 M. Previous experiments (Sandhu et of 50 M was identified and used in the present studies.
al., 2003) reported that concentration of 10–100 M After 24 h exposition of CaCo-2 cells to CoQ10 ,
did not have significant cellular effects. To further de- gene array technology revealed changes in mRNA-
fine the optimal concentration, the apoptosis-related ef- levels for 694 out of 10,000 genes in the presence
fects of CoQ10 was examined using caspase-3 activity of a cut off value of >2-fold. Interestingly, no genes
as early phase and DNA fragmentation as late phase were down-regulated >2-fold and only one gene wasD.A. Groneberg et al. / The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218 1215
down-regulated 1.5–2-fold. The different genes can This finding may indicate a participation of gene
be at least classified into eight functional subgroups interactions of CoQ10 in the suppression of initial steps
including genes involved in cell signalling (n = 79), of the apoptosis cascade which is especially related to
metabolism (n = 58), transport (n = 47), transcription effects on the caspase-3 activity (Fernandez-Ayala et
(n = 32), disease mutation (n = 24), phosphorylation al., 2000; Navas et al., 2002).
(n = 19), embryonal development (n = 13) and binding Several reports describe both clinical and biochem-
(n = 9). While the genes classified by these groups cover ical improvement in patients with mitochondrial disor-
41% of the identified genes; 16% of the genes (n = 111) ders (Abe et al., 1991; Bresolin et al., 1988; Shoffner et
encode for proteins with miscellaneous functions and al., 1989). If defects in energy metabolism and oxida-
a large portion (n = 298) encodes for proteins with un- tive damage play a role in the pathogenesis of neurode-
known function. generative diseases (Beal, 2002, 2004), then treatment
To validate the quality of the presently used array with coenzyme CoQ10 could exert beneficial therapeu-
technology, post array analysis was performed for a se- tic effects. It has been also shown, that CoQ10 admin-
lected number of genes. In this respect, real-time PCR istration increases brain mitochondrial concentrations
experiments were performed for eight selected genes (Kamzalov, Sumien, Forster & Sohal, 2003; Kwong
from different clusters and changes in the expression et al., 2002; Matthews et al., 1998) and exerts neu-
level were confirmed for seven genes. roprotective effects (Matthews et al., 1998). CoQ10 is
The function of some of the differently regulated also able to attenuate the loss of dopaminergic neurons
genes can be related to the known effects of CoQ10 . in Parkinson’s disease (Beal & Shults, 2003; Ebadi
It is recognized as an essential cofactor in the elec- et al., 2001; Shults et al., 2002). We found an effect
tron transport chain process of uncoupling proteins and of CoQ10 on the regulation of the two genes guanine
serves as an important antioxidant in both mitochon- nucleotide binding protein, alpha activating activity
dria and lipid membranes. CoQ10 participates in the polypeptide o and guanine nucleotide binding protein,
transfer of electrons from complex I to complex III alpha z polypeptide. Both have been attributed a crucial
which is an obligatory process used in many mem- role in the development and progression of Alzheimer’s
branes and the administration of CoQ10 has also been disease. Also, hypothetical protein mgc 3358 which
demonstrated to increase H+ transport (Echtay et al., was presently found to be regulated by CoQ10 has been
2001). With regard to these biological functions of the proposed to play a role in Huntington’s disease. An ef-
cofactor, many of the genes found to be up-regulated fect of CoQ10 has also been postulated on the course of
in the present study are also known to participate in the metabolic disorders such as diabetes (Hodgson, Watts,
transport functions in which coenzyme Q is involved. Playford, Burke & Croft, 2002; Playford, Watts, Croft
These genes include purine nucleoside phosphorylase, & Burke, 2003). We found a regulation of transcription
poly (adp-ribosyl) transferase-like 1 or ribonuclease, factor 2 that has previously been related to diabetes.
rnase family, 2. Recently, microarray and proteome analysis has
A further class of genes which was shown to respond been employed to identify genes or proteins regulated
to CoQ10 is represented by embryonal developmental by CoQ10 in human skeletal muscle (Linnane et al.,
genes. In this respect, it was earlier reported that CoQ10 , 2002). That approach represents a clinical trial on the
is a crucial factor for the embryonal development of effect of CoQ10 administration on human vastus lat-
mice (Levavasseur et al., 2001). Presently identified eralis (quadriceps) skeletal muscle samples, obtained
CoQ10 , regulated genes such as disabled homolog 1 from aged individuals receiving placebo or CoQ10 -
or orthodenticle homolog 2 are know to participate in supplementation (300 mg per day for 4 weeks prior
the development of the central nervous system and the to hip replacement surgery). With a cut off point of
sensor organs of man and mice. 1.8-fold or greater a total of 115 genes were found
Seven genes that were regulated by CoQ10 are to be differentially expressed in six subject compar-
known to participate in apoptosis processes. They in- isons. In the CoQ10 -treated subjects, 47 genes were up-
clude apoptosis antigen 1, which participates in the in- regulated and 68 were down-regulated in comparison
duction of apoptosis and cd27 antigen, that displays an with placebo-treated subjects. A further recent studies
inhibitory factor of caspase activity. assessed the impact of alpha-lipoic acid, coenzyme Q101216 D.A. Groneberg et al. / The International Journal of Biochemistry & Cell Biology 37 (2005) 1208–1218
and caloric restriction gene expression patterns in mice fects on transcriptional gene regulation (Rimbach et
by monitoring the expression of 9977 genes in hearts al., 2002) and it has been reported that Vitamin E leads
from young (5 months) and old (30 months) mice (Lee to the induction rather than the inhibition of transcrip-
et al., 2004). tional expression of many genes. We here found that
The present approach differs to these in vivo inter- similar to the effects of Vitamin E, most genes were
ventional studies in that it used a molecular well defined up-regulated by CoQ10 . In this respect, it could be hy-
cell type line. This allowed a clear definition of CoQ10 pothesized that Vitamin E and CoQ10 as antioxidants
effects on a single human cell type that may serve as trigger reactive oxygen species-sensitive intracellular
model of gastrointestinal epithelial cells, the cells that pathways that regulate the induction of specific genes.
come first in contact with nutritionally administered In conclusion, our findings indicate that CoQ10 may
CoQ10 . Therefore, in comparison to complex tissues exert many of its effects via the induction of gene tran-
as found in muscle biopsies containing myocytes, fi- scription and therefore acts as a potent gene regulator.
broblasts, endothelial cells, vascular smooth muscle The presently identified comprehensive list of genes
myocytes and blood cells, our approach uses a homoge- regulated by CoQ10 may be used for further studies to
nous cell population under standardized conditions to dissect further molecular mechanism of CoQ10 actions.
identify CoQ10 sensitive genes. Comparing the results
obtained by the muscle biopsies array with the present
array data, some differences are found. Up-regulated Acknowledgements
genes in the muscle biopsy study include glutamate re-
ceptor protein GluR5, fibroblast growth factor receptor We thank Prof. H. Daniel for helpful discussions and
N-SAM, protein kinase C-epsilon or guanylyl cyclase. continuous support. Grant support: Supported by the
Due to the imprecise terminology of the genes with- International Coenzyme Q10 Association.
out exact accession numbers, a detailed comparison
is only partly possible. The present experiments con-
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