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Effects of Betaine Intake on Plasma Homocysteine Concentrations and Consequences for Health


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High plasma concentrations of homocysteine may increase risk of cardiovascular disease. Folic acid lowers plasma homocysteine by 25% maximally, because 5-methyltetrahydrofolate is a methyl donor in the remethylation of homocysteine to methionine. Betaine (trimethylglycine) is also a methyl donor in homocysteine remethylation, but effects on homocysteine have been less thoroughly investigated. Betaine in high doses (6 g/d and higher) is used as homocysteine-lowering therapy for people with hyperhomocysteinemia due to inborn errors in the homocysteine metabolism. Betaine intake from foods is estimated at 0.5-2 g/d. Betaine can also be synthesized endogenously from its precursor choline. Studies in healthy volunteers with plasma homocysteine concentrations in the normal range show that betaine supplementation lowers plasma fasting homocysteine dose-dependently to up to 20% for a dose of 6 g/d of betaine. Moreover, betaine acutely reduces the increase in homocysteine after methionine loading by up to 50%, whereas folic acid has no effect. Betaine doses in the range of dietary intake also lower homocysteine. This implies that betaine can be an important food component that attenuates homocysteine rises after meals. If homocysteine plays a causal role in the development of cardiovascular disease, a diet rich in betaine or choline might benefit cardiovascular health through its homocysteine-lowering effects. However betaine and choline may adversely affect serum lipid concentrations, which can of course increase risk of cardiovascular disease. However, whether the potential beneficial health effects of betaine and choline outweigh the possible adverse effects on serum lipids is as yet unclear.
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Current Drug Metabolism, 2005, 6, 15-22 15
1389-2002/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.
Effects of Betaine Intake on Plasma Homocysteine Concentrations and
Consequences for Health
M.R. Olthof
and P. Verhoef
Wageningen Centre for Food Sciences and Wageningen University, Division of Human Nutrition, Wageningen, the
Abstract: High plasma concentrations of homocysteine may increase risk of cardiovascular disease. Folic acid lowers
plasma homocysteine by 25% maximally, because 5-methyltetrahydrofolate is a methyl donor in the remethylation of
homocysteine to methionine. Betaine (trimethylglycine) is also a methyl donor in homocysteine remethylation, but effects
on homocysteine have been less thoroughly investigated. Betaine in high doses (6 g/d and higher) is used as
homocysteine-lowering therapy for people with hyperhomocysteinemia due to inborn errors in the homocysteine
metabolism. Betaine intake from foods is estimated at 0.5-2 g/d. Betaine can also be synthesized endogenously from its
precursor choline. Studies in healthy volunteers with plasma homocysteine concentrations in the normal range show that
betaine supplementation lowers plasma fasting homocysteine dose-dependently to up to 20% for a dose of 6 g/d of
betaine. Moreover, betaine acutely reduces the increase in homocysteine after methionine loading by up to 50%, whereas
folic acid has no effect. Betaine doses in the range of dietary intake also lower homocysteine. This implies that betaine can
be an important food component that attenuates homocysteine rises after meals. If homocysteine plays a causal role in the
development of cardiovascular disease, a diet rich in betaine or choline might benefit cardiovascular health through its
homocysteine-lowering effects. However betaine and choline may adversely affect serum lipid concentrations, which can
of course increase risk of cardiovascular disease. However, whether the potential beneficial health effects of betaine and
choline outweigh the possible adverse effects on serum lipids is as yet unclear.
Key Words: Betaine, choline, homocysteine, health, human.
Betaine (N, N, N-trimethylglycine) is a quaternary amine
that occurs naturally in cells to protect them against osmotic
stress. Betaine can also be synthesized endogenously through
oxidation of excess choline. Choline is required for synthesis
of phospholipids in cell membranes, cholinergic neuro-
transmission and for methyl metabolism through betaine [1].
Betaine helps to maintain normal cell volume, e.g. in the
kidney, and it serves as methyl donor for the remethylation
of homocysteine into methionine, catalyzed by the enzyme
betaine-homocysteine methyltransferase (BHMT) (Fig. (1))
[2]. Methionine is metabolized into homocysteine, via
demethylation of S-adenosylmethionine (SAM). High total
homocysteine (tHcy) concentrations may lead to cardio-
vascular disease [3], pregnancy complications [4], and
cognitive decline in elderly [5-7]. The most potent food
component that reduces thcy concentrations is the B-vitamin
folate: the vitamer 5-methyltetrahydrofolate is also a methyl
donor in the (re)methylation of homocysteine to methionine
[8]. Additionally, supplementation with other B vitamins
such as cobalamin (vitamin B
) and pyridoxine (vitamin B
can also reduce tHcy concentrations, but to a much lower
extent than folic acid [9, 10].
Now that the US food supply is fortified with folic acid,
the interest in homocysteine-lowering nutrients in addition to
*Address correspondence to this author at the Wageningen Centre for Food
Sciences and Wageningen University, Division of Human Nutrition, PO box
8129, 6700 EV, Wageningen, the Netherlands; Fax: +31-317-483342;
folic acid will increase. Betaine and its precursor choline are
potential candidates. Large amounts of betaine are already
given as oral therapy to patients with inborn errors that lead
to very high thcy concentrations in blood, even though little
is known about the metabolism of betaine in humans.
Homocysteine is metabolized by two methionine con-
serving remethylation reactions (Fig. (1)): 1) by means of
methionine synthase (MS), with 5-methyltetrahydrofolate as
methyl donor; and 2) by means of BHMT, with betaine as
methyl donor. Methionine is important for protein synthesis,
and it is a source of methyl groups through formation of
SAM. SAM is a universal methyl donor in many reactions
catalyzed by methyltransferases [11]. Homocysteine can
also be broken down into cysteine via the transsulfuration
Betaine is either consumed through foods, or formed
endogenously out of its precursor choline. Catabolism of bet-
aine provides 3 methyl groups to the one-carbon pool. One
of these methyl groups becomes available for remethylation
of homocysteine into methionine, in a reaction catalyzed by
BHMT. The other 2 methyl groups from betaine enter the
folate pool for formation of 5, 10-methylenetetrahydrofolate
in mitochondria [2, 12, 13]. The end-product of betaine cata-
bolism, glycine, is used as a methyl acceptor for S-adeno-
sylmethionine (SAM) when SAM concentrations become too
high. Glycine N-methyltransferase (GNMT) catalyzes this
reaction [14].
16 Current Drug Metabolism, 2005, Vol. 6, No. 1 Olthof and Verhoef
Remethylation through the BHMT pathway is confined
to the liver and kidney [2]. In contrast with that, remethyla-
tion of homocysteine catalyzed by MS occurs in all body
cells. Both remethylation pathways are metabolically
interrelated [12]. Rats that were maintained on a choline-
deficient diet for 2 weeks have 31% lower hepatic folate
content [15]. Moreover, rats maintained on a folate-deficient
diet also induced depletion of hepatic choline [16]. This
suggests that limitation of one pathway increases remethyla-
tion via the other pathway. In line with this, we found that
supplementation with folic acid doses increases fasting
plasma betaine concentrations in healthy elderly (Melse-
Boonstra et al., unpublished). In addition, supplementation
with B-vitamins attenuates the initial inverse association
between plasma betaine concentrations and post-methionine
thcy concentrations in coronary patients [17]. On the other
hand, 6 weeks of betaine supplementation does not affect
folate concentrations in adults with mildly elevated tHcy
concentrations supplemented with 6 g betaine per day [18]. It
could be that, instead of the folate concentrations, the
concentration of the amino acid serine is increased through
betaine supplementation, but this was not measured. Serine
is the actual methyl donor in the synthesis of 5-
methyltetrahydrofolate, which makes folate more a methyl
carrier (Fig. (1)) [19]. Overall, this indicates that increased
remethylation of homocysteine via MS down regulates the
remethylation through the BHMT dependent pathway.
Betaine is present in several plants as an osmolyte that
protects against unfavorable environmental conditions, such
as high levels of salt or low temperature. Betaine has similar
functions in some organs of mammals. As a result betaine is
present in various plant foods and in meat. Recently a
database with information on amounts of betaine and choline
derivatives in various foods became available [20]. The
dietary intake of betaine is estimated at 0.5-2 g/d, and of
choline at 0.3-1 g/d [21, 22]. With the database it would now
be possible to determine daily intakes of betaine and choline
in different populations. However, it is unknown to the
authors whether this is currently being investigated.
Fig. (1). Schematic overview of the role of betaine, choline and folic acid in homocysteine metabolism.
Effects of Betaine Intake on Plasma Homocysteine Current Drug Metabolism, 2005, Vol. 6, No. 1 17
Foods rich in betaine are spinach, beets, shrimp and
wheat products. Interestingly, many wines contain betaine in
low levels, particularly less expensive wines because beet
sugar is used to increase the alcohol content [23]. Betaine is
a by-product of sugar production from sugar beets and it is
used in food industry as food additive.
Foods rich in choline are in eggs, liver, soybeans and
pork. Choline is present in foods mostly as lecithin [21, 22].
Lecithin is actually a mixture of phospholipids and it con-
tains about 30% phosphatidylcholine. Lecithin is also added
to commercial foods as an emulsifying agent.
Betaine and choline are also available as dietary supple-
ments for several purposes, e.g. heart health through homo-
cysteine lowering, digestive aid, liver protection, cognition,
and physical performance. However their actual effective-
ness is questionable.
In observational studies plasma betaine concentrations
are inversely associated with fasting homocysteine
concentrations in cardiovascular patients [24]. In addition,
plasma betaine is a determinant of the increase in plasma
homocysteine after methionine loading [17].
The effect of betaine and choline supplementation on
lowering of plasma concentration of thcy has mainly been
studied in clinical settings [25-30]. Betaine is considered a
safe and effective therapy to lower thcy in patients with
inborn errors in the enzymes involved in homocysteine
metabolism, e.g. diminished activity of cystathionine beta-
synthase (CBS), who are not responsive to pyridoxine treat-
ment [31]. Generally, large amounts of betaine are added to
the regimen to lower thcy because low doses were not
effective [32]. Betaine doses of up to 20 g per day (the most
commonly used dose was 2 x 3 g betaine/day) drastically
lower fasting and post-methionine plasma thcy levels to
near-normal levels. The onset of homocysteine-lowering is
within several days and long-term supplementation with
betaine remains effective for years [31]. In contrast to the
effects of betaine in the patients with genetically caused
hyperhomocysteinemia, supplementation with 4-6 g/d of
betaine in addition to folic acid therapy (1-5 mg/d folic acid)
for 1 week to 3 months does not affect fasting or post-
methionine loading thcy concentrations in hemodialysis
patients (Table 1). The authors concluded that higher
dosages of betaine or folic acid might be needed to
normalize plasma thcy concentrations in these patients [33,
34]. McGregor et al., [35] also found that 4 g/d of betaine in
addition to folic acid and pyridoxine therapy for 3 months
has no additional effect on fasting plasma thcy in patients
with chronic renal failure. However, in their study betaine
supplementation does suppress the increase in thcy concen-
trations following methionine loading by 18%, relative to
folic acid and pyridoxine treatment alone. Thus the effect of
betaine on thcy lowering is not consistent in these clinical
studies. Moreover, all these studies are done in patients with
fasting thcy concentrations far above normal. Recently data
became available about the effects of betaine supplemen-
tation in healthy subjects with normal thcy concentrations.
In healthy volunteers with normal thcy concentrations
supplementation with 6 g/d of betaine for 6-12 weeks lowers
fasting thcy concentrations up to 20% relative to placebo
(Table 1) [18, 36, 37]. In addition, taking betaine together
with a methionine loading test (100 mg/kg body weight)
reduces the increase in thcy after a methionine load by up of
50%, whereas folic acid has no effect [18, 37] (Fig. (2)). This
implies that adding betaine to foods that potentially increase
thcy concentrations, (e.g. protein-rich foods, which are high
in methionine) helps to attenuate homocysteine rises after
meals. Consequently, the risk of cardiovascular disease
might be reduced since the increase in plasma thcy after
methionine loading is a risk indicator for cardiovascular
disease independent from fasting thcy concentrations [38,
39]. The lack of an effect of folic acid on post-methionine
plasma homocysteine might be due to the rise in SAM after
methionine loading, which suppresses activity of 5, 10-
methylenetetrahydrofolate reductase (MTHFR), and thereby
production of 5-methyltetrahydrofolate [40]. Hence, the
remethylation pathway via folate is hindered. The
concentration of SAM does not seem to influence the
remethylation via the betaine remethylation pathway.
The dose of 6 g/d of betaine used in the intervention
studies and in therapeutic settings cannot be easily attained
through normal food consumption. Normal betaine intake is
estimated at 0.5-2 g/d. A betaine dose of 6 g is in ~0.8 kg of
cooked spinach or ~2.6 kg of wheat bread [20]. We therefore
investigated the effect of betaine doses lower than 6 g/d on
plasma homocysteine concentrations. In a parallel study we
gave 1.5 g/d, 3 g/d, 6 g/d of betaine, or placebo to 19 healthy
subjects per dose group for 6 weeks. We measured fasting
plasma homocysteine at baseline, and after 2 and 6 weeks of
intervention. We also measured plasma homocysteine
responses after methionine loading at baseline, and on day 1,
and after 2 and 6 weeks of intervention. We found that there
is a dose-response relation between betaine doses up to 6 g/d
and plasma thcy responses (Fig. (3)) [37]. The dose of
betaine in the dietary range (1.5 g/d) lowers fasting thcy by
12% and plasma thcy concentrations 6 h after methionine
loading by 23% in healthy volunteers. In addition, a single
dose of 0.75 g of betaine together with a methionine load on
the first day of supplementation acutely reduces the increase
in plasma thcy 6 h after methionine loading by 16%. The
acute effect of betaine on homocysteine is in line with the
pharmacokinetics of betaine in humans. Betaine is very
rapidly absorbed, distributed and metabolized into dimethyl-
glycine, indicated by an increase in dimethylglycine concen-
tration after intake of betaine [41, 42]. This suggests that
exogenous betaine is quickly available as methyl donor after
oral intake.
Because betaine is also endogenously formed out of
choline, choline supplementation could influence the produc-
tion of betaine, the flux through the BHMT-remethylation,
and homocysteine concentrations [43, 44]. However data on
effects of choline intake on plasma thcy concentrations in
humans are limited. We investigated the effect of choline
supplementation for 2 weeks on fasting and post-methionine
plasma homocysteine in a cross over study in 26 male volun-
18 Current Drug Metabolism, 2005, Vol. 6, No. 1 Olthof and Verhoef
teers. Preliminary results show that choline supplementation
can lower plasma thcy responses in men (Olthof et al.,
Thus, low thcy levels can be achieved through specific
betaine and/or choline (en)rich(ed) foods. Whether low
homocysteine concentrations are beneficial for health is still
not sure. On the other hand, betaine might adversely affect
serum lipids.
In contrast to the potential beneficial homocysteine-
lowering properties of betaine, human studies show that
betaine supplementation adversely affects serum lipid
concentrations. Supplementation of 4 g/d of betaine in
addition to B-vitamins for 3 months in patients with chronic
renal failure increases total serum cholesterol, LDL, HDL
and triacylglycerol concentrations up to 10%, relative to
treatment with B-vitamins alone [35]. Supplementation of 6
g/d of betaine for 12 weeks in obese subjects who are on a
weight loss diet increases serum total cholesterol and LDL
cholesterol up to 14% relative to the placebo group. Serum
triacylglycerol concentrations increased by ~12%, but this
was not statistically significant [36]. Our own studies
confirm that betaine supplementation for 6 weeks increases
serum total cholesterol, especially LDL, in healthy humans
(Olthof et al., unpublished). Unfortunately there are no data
on changes in cholesterol concentrations in hyperhomo-
cysteinemic patients who are on betaine treatment. Probably
in these patients the benefits of the drastic reduction in thcy
will outweigh the adverse effects on plasma cholesterol
concentrations. However, it might be important to monitor
serum cholesterol concentrations in patients on betaine
treatment, and treat them if their cholesterol concentrations
The precursor of betaine, choline is also involved in lipid
metabolism. Choline in the form of phosphatidylcholine
plays an important role in the maintenance of normal lipid
transport. Choline deficiency in humans decreases serum
cholesterol by 15%, and increases fat accumulation in the
liver [45]. In addition, patients receiving long-term paren-
teral nutrition without choline had very low total cholesterol
concentrations, especially LDL cholesterol [46]. Adding
choline to the diet reversed liver problems in these patients
on parenteral nutrition and in healthy humans.
Table 1. Intervention Trials Investigating the Effect of Betaine on Plasma tHcy in Humans
Reference Subjects Design Effect on tHcy
v. Guldener et al.
Parallel, intervention for 12 weeks:
1. placebo (n=18)
2. 4 g/d betaine (n=17)
All subjects received 5 mg/d folic acid +
50 mg pyridoxine during the study
Fasting tHcy decreased from 48.4 µmol/L to 17.4
Post-methionine tHcy decreased from 94.3 µmol/L to
48.3 µmol/L
Betaine had no additional homocysteine-lowering
Mc Gregor et al.
Patients with
chronic renal
Cross over, n=36, intervention for 3 months:
1. placebo
2. 4 g/d betaine
All subjects received 5 mg/d folic acid +
50 mg pyridoxine during the study
Fasting tHcy decreased to the same extent with both
treatments relative to baseline.
Post-methionine tHcy decreased with both treatments,
but was 18% lower on betaine than on placebo.
Schwab et al.
Obese men and
Parallel, intervention for 12 weeks:
1. placebo (n=20)
2. 6 g/d betaine (n=22)
All subjects were on a weight loss diet
Fasting tHcy decreased by ~11% (from 8.76 to 7.93
µmol/L) in the betaine group relative to the placebo
Steenge et al.
Healthy men and
Parallel, n=12 per group, intervention for 6 weeks:
1. Placebo
2. 800 µg/d folic acid
3. 6 g/d betaine
Fasting tHcy decreased by 11% (from 12.2 to 10.9
µmol/L) in the betaine group and by 18% (from 13.0 to
10.7 µmol/L) in the folic acid group.
Post-methionine tHcy decreased by 49% in the betaine
group, whereas folic acid had no effect.
Olthof et al.
Healthy men and
Parallel, n=19 per group, intervention for 6 weeks:
1. Placebo
2. 1.5 g/d betaine
3. 3 g/d betaine
4. 6 g/d betaine
Fasting tHcy was 12%, 15% and 20% lower in the 1.5
g/d, 3 g/d and 6 g/d betaine groups than in the placebo
group respectively.
Post-methionine tHcy was 23%, 30% and 40% lower
than in the placebo group after subjects had ingested 1.5
g/d, 3 g/d, and 6 g/d betaine for 6 weeks respectively.
The homocysteine-lowering effect of a single dose
(which was half the daily dose) of betaine after
methionine loading was similar to the effect after 6
weeks intervention.
Effects of Betaine Intake on Plasma Homocysteine Current Drug Metabolism, 2005, Vol. 6, No. 1 19
Supplementation with choline in rats increases serum
cholesterol concentrations [47, 48]. The effects of supple-
mentation with choline, on serum lipid concentrations in
humans are uncertain, but an increase in serum lipids is
expected [22]. We found in a cross over study in 26 healthy
men that choline supplementation for 2 weeks increases
serum triacylglycerol concentrations, but had no effect on
serum cholesterol concentrations (Olthof et al., unpublished).
However, 2 weeks supplementation of choline might have
been too short to find the effect of choline on serum
The mechanism by which betaine and choline may
increase serum lipid concentrations probably involves
increased transport of lipids from the liver into the serum.
Lipids are exported from the liver in the form of Very Low
Density Lipoproteins (VLDL). Betaine or choline supple-
mentation might increase the synthesis of VLDL through an
increase in phosphatidylcholine synthesis, which is an
Fig. (2). Plasma thcy responses in humans after the ingestion of 100 mg methionine/kg body mass A) before and B) after 6 weeks of
treatment. Treatments consisted of the ingestion of 3 g of betaine (n = 12), 400 µg folic acid, (n = 12) or 3 g of placebo (n = 9) twice each
day. Values are means ± SEM. Adapted from Steenge et al. [18].
Fig. (3). A) Mean fasting plasma thcy concentrations (µmol/L) at baseline, and after 2 and 6 weeks of treatment with different betaine doses
in 19 healthy volunteers per dose group. B) Mean increase in plasma thcy concentrations (µmol/L) from 0-6 h after methionine loading at
baseline, on the first day, and after 2 and 6 weeks of treatment. Treatments consisted of ingestion of 0.75 g of betaine, 1.5 g of betaine, 3 g of
betaine, or 3 g of placebo twice each day. All subjects ingested half of the daily dose of betaine together with the methionine load [37].
20 Current Drug Metabolism, 2005, Vol. 6, No. 1 Olthof and Verhoef
essential component of VLDL [49]. Consequently, more
VLDL will lead to increased transport of lipids from the liver
into the serum, whereby concentrations of lipids in the liver
decrease accordingly [50]. Phosphatidylcholine synthesis can
be influenced through 2 pathways. Betaine and choline can
affect either pathway (Fig. (4)). Choline can be directly
metabolized into phosphatidylcholine. Secondly, betaine and
choline might increase availability of SAM via increased
remethylation of homocysteine into methionine. SAM is the
methyl donor for the formation of phosphatidylcholine via
sequential methylation of phosphatidylethanolamine [51].
The hypothesis as stated above could mean that other
dietary methyl donors that increase SAM potentially might
increase serum lipids as well, but no data are available on
this. In conclusion, betaine and choline supplementation
might lead to increases in serum lipid concentrations, which
is not beneficial for health.
A high plasma homocysteine is a potential risk for
cardiovascular disease. Betaine supplementation lowers
fasting plasma thcy in healthy subjects by 15-20%, and
plasma thcy after methionine loading by 20-40% [18, 37].
For example, a person who consumes a diet rich in
betaine (~2 g/d of betaine) has ~12% lower plasma thcy than
a person who consumes a diet poor in betaine (0.5 g/d) [37].
A 25% reduction in thcy concentrations is associated with
11% lower risk of ischemic heart disease, and 19% lower
risk of stroke [7]. Based on this, a betaine-rich diet would
reduce cardiovascular disease risk by 5-10% relative to a
betaine-poor diet.
Whether homocysteine lowering indeed lowers risk of
cardiovascular diseases is not yet established, but evidence
for a causal relationship is accumulating [52-54]. In a meta-
analysis Klerk et al., [55] found that subjects with the
MTHFR-TT genotype have a 16% higher risk of coronary
heart disease. The MTHFR 677C-->T polymorphism is a
genetic alteration in an enzyme involved in folate meta-
bolism that causes elevated thcy concentrations. Because a
relationship between a genotype and disease cannot be
confounded by lifestyle, this study provides strong evidence
for a causal relationship between high homocysteine and risk
of cardiovascular disease. In contrast, two secondary preven-
tion trials show no reduction of coronary heart disease or
stroke after ~2 y homocysteine-lowering treatment [56]
Baker et al., 2002]. In several years from now there will be
data from about 50.000 patients that were allocated to B
vitamins or placebo [57]. However, all treatments in these
trials with B-vitamins include folic acid, which will make it
impossible to distinguish between the effects of folic acid
itself and the effects of homocysteine lowering per se. Only
intervention studies with homocysteine-lowering agents
other than folic acid, for example betaine, will help to
investigate the effect of homocysteine lowering per se on
disease risk. We used this approach in two studies in order to
investigate the effects of homocysteine-lowering per se on
endothelial function in healthy volunteers (Olthof et al.,
unpublished). Endothelial function can be considered a
surrogate endpoint for cardiovascular risk [58-61]. In our
studies we compare the effect of homocysteine-lowering via
folic acid supplementation with that via betaine supplemen-
tation on endothelial function in healthy volunteers.
The effects of betaine or choline intakes on cardio-
vascular morbidity or mortality are unknown. Observational
studies are now possible with the available database with
contents of betaine and choline in various foods [20].
However, it is unknown to the authors whether this is
currently being investigated. It will be important to realize
that a potential health benefit of betaine and choline through
thcy lowering might vanish, since betaine and its precursor
choline potentially increase serum lipids.
The interest in betaine and its precursor choline as
homocysteine-lowering agents is increasing. We have shown
that betaine doses in the range of normal dietary intake can
lower fasting plasma thcy as well as plasma thcy after
methionine loading in healthy volunteers. The unique
properties of betaine relative to folic acid are that betaine
suppresses the increase in thcy after a methionine loading,
Baker, F., Picton, D., Blackwood, S., Hunt, J., Erskine, M., Dyas, M., Ashby, M.,
Siva, A. & Brown, M.J. (2002) Circulation 106 (suppl II), 741 (abstract).
Fig. (4). The potential role of choline and betaine in phosphatidylcholine metabolism. Phosphatidylcholine is necessary for synthesis of
VLDL, which exports lipids from the liver.
Effects of Betaine Intake on Plasma Homocysteine Current Drug Metabolism, 2005, Vol. 6, No. 1 21
and that this occurs acutely. Therefore betaine is a promising
agent to suppress increases in thcy after meals. Betaine and
choline occur naturally in various foods. If betaine and
choline prove to be beneficial for health it might also be
interesting to produce foods high in betaine or choline by
adding these compounds, or through genetic engineering
techniques. For betaine, these techniques are in principle
already available to produce plants, such as spinach and
barley, with high amounts of betaine to improve growth of
these plants under high stress conditions worldwide [62]. A
diet rich in betaine and choline could be beneficial for health,
if homocysteine proves to be a causal factor in the
development of cardiovascular disease. However, there are
indications that high betaine and choline intakes increase
serum lipid concentrations, which of course increases risk of
cardiovascular disease. Because the overall impact of betaine
and choline on health is unclear, ingestion of extra betaine or
choline through foods rich in these compounds, or through
supplements is not recommended. Studies on the effects of
betaine and choline on risk of cardiovascular disease are
needed before we can judge the health effects of betaine and
choline intakes.
BHMT =Betaine-homocysteine methyltransferase
HDL =High Density Lipoproteins
LDL =Low Density Lipoproteins
MS =Methionine synthase
MTHFR =5, 10-methylenetetrahydrofolate reductase
SAM =S-adenosylmethionine
tHcy =Total homocysteine
VLDL =Very Low Density Lipoproteins
[1] Zeisel, S.H. and Blusztajn, J.K. (1994) Annu. Rev. Nutr., 14, 269-
[2] Garrow, T.A. (2001) In Homocysteine in health and disease,
(Carmel, R. and Jacobsen, D.W.Eds.), Cambridge University Press,
Camebridge, pp. 145-152.
[3] Wald, D.S.; Law, M. and Morris, J.K. (2002) BMJ, 325(7374),
[4] Nelen, W.L. (2001) Clin. Chem. Lab. Med., 39(8), 758-763.
[5] Seshadri, S.; Beiser, A.; Selhub, J.; Jacques, P.F.; Rosenberg, I.H.;
D'Agostino, R.B.; Wilson, P.W. and Wolf, P.A. (2002) N. Engl. J.
Med., 346(7), 476-483.
[6] Duthie, S.J.; Whalley, L.J.; Collins, A.R.; Leaper, S.; Berger, K.
and Deary, I.J. (2002) Am. J. Clin. Nutr., 75(5), 908-913.
[7] Homocysteine Studies Collaboration. (2002) JAMA, 288(16), 2015-
[8] Anonymous. (1998) BMJ, 316(7135), 894-898.
[9] Ubbink, J.B.; Vermaak, W.J.; van der Merwe, A.; Becker, P.J.;
Delport, R. and Potgieter, H.C. (1994) J. Nutr., 124(10), 1927-
[10] Clarke, R. and Armitage, J. (2000) Semin. Thromb. Hemost., 26(3),
[11] Finkelstein, J.D. and Martin, J.J. (1986) J. Biol. Chem., 261(4),
[12] Niculescu, M.D. and Zeisel, S.H. (2002) J. Nutr., 132(8 Suppl),
[13] Allen, R.H.; Stabler, S.P. and Lindenbaum, J. (1993) Metabolism,
42(11), 1448-1460.
[14] Rowling, M.J.; McMullen, M.H.; Chipman, D.C. and Schalinske,
K.L. (2002) J. Nutr., 132(9), 2545-2550.
[15] Selhub, J.; Seyoum, E.; Pomfret, E.A. and Zeisel, S.H. (1991)
Cancer Res., 51(1), 16-21.
[16] Kim, Y.I.; Miller, J.W.; Da Costa, K.A.; Nadeau, M.; Smith, D.;
Selhub, J.; Zeisel, S.H. and Mason, J.B. (1994) J. Nutr., 124(11),
[17] Holm, P.I.; Bleie, O.; Ueland, P.M.; Lien, E.A.; Refsum, H.;
Nordrehaug, J.E. and Nygard, O. (2004) Arterioscler. Thromb.
Vasc. Biol., 24(2), 301-307.
[18] Steenge, G.R.; Verhoef, P. and Katan, M.B. (2003) J. Nutr., 133(5),
[19] Davis, S.R.; Stacpoole, P.W.; Williamson, J.; Kick, L.S.;
Quinlivan, E.P.; Coats, B.S.; Shane, B.; Bailey, L.B. and Gregory,
J.F. (2004) Am. J. Physiol. Endocrinol. Metab., 286(2), E272-E279
[20] Zeisel, S.H.; Mar, M.H.; Howe, J.C. and Holden, J.M. (2003) J.
Nutr., 133(5), 1302-1307.
[21] Canty, D.J. and Zeisel, S.H. (1994) Nutr. Rev., 52(10), 327-339.
[22] Zeisel, S.H. (1981) Annu. Rev. Nutr., 1, 95-121.
[23] Mar, M.H. and Zeisel, S.H. (1999) Med. Hypotheses., 53(5), 383-
[24] Schwahn, B.C.; Chen, Z.; Laryea, M.D.; Wendel, U.; Lussier-
Cacan, S.; Genest, J.J.; Mar, M.H.; Zeisel, S.H.; Castro, C.;
Garrow, T. and Rozen, R. (2003) FASEB J., 17(3), 512-514.
[25] Perry, T.L.; Hansen, S.; Love, D.L.; Crawford, L.E. and Tischler,
B. (1968) Lancet, 2(7566), 474-478.
[26] Smolin, L.A.; Benevenga, N.J. and Berlow, S. (1981) J. Pediatr.,
99(3), 467-472.
[27] Wilcken, D.E.; Wilcken, B.; Dudman, N.P. and Tyrrell, P.A.
(1983) N. Engl. J. Med., 309(8), 448-453.
[28] Wilcken, D.E.; Dudman, N.P. and Tyrrell, P.A. (1985) Metabolism,
34(12), 1115-1121.
[29] Sakura, N.; Ono, H.; Nomura, S.; Ueda, H. and Fujita, N. (1998) J.
Inherit. Metab. Dis., 21(1), 84-85.
[30] Singh, R.H.; Kruger, W.D.; Wang, L.; Pasquali, M. and Elsas, L.J.
(2004) Genet. Med., 6(2), 90-95.
[31] Wilcken, D.E. and Wilcken, B. (1997) J. Inherit. Metab. Dis.,
20(2), 295-300.
[32] Brenton, D.P.; Cusworth, D.C.; Dent, C.E. and Jones, E.E. (1966)
Q. J. Med., 35(139), 325-346.
[33] van Guldener, C.; Janssen, M.J.; de Meer, K.; Donker, A.J. and
Stehouwer, C.D. (1999) J. Intern. Med., 245(2), 175-183.
[34] Bostom, A.G.; Shemin, D.; Nadeau, M.R.; Shih, V.; Stabler, S.P.;
Allen, R.H. and Selhub, J. (1995) Atherosclerosis, 113(1), 129-132.
[35] McGregor, D.O.; Dellow, W.J.; Robson, R.A.; Lever, M.; George,
P.M. and Chambers, S.T. (2002) Kidney Int., 61(3), 1040-1046.
[36] Schwab, U.; Torronen, A.; Toppinen, L.; Alfthan, G.; Saarinen, M.;
Aro, A. and Uusitupa, M. (2002) Am. J. Clin. Nutr., 76 (5), 961-
[37] Olthof, M.R.; van Vliet, T.; Boelsma, E. and Verhoef, P. (2003) J.
Nutr., 133(12), 4135-4138.
[38] Graham, I.M.; Daly, L.E.; Refsum, H.M.; Robinson, K.;
Brattstrom, L.E.; Ueland, P.M.; Palma-Reis, R.J.; Boers, G.H.;
Sheahan, R.G.; Israelsson, B.; Uiterwaal, C.S.; Meleady, R.;
McMaster, D.; Verhoef, P.; Witteman, J.; Rubba, P.; Bellet, H.;
Wautrecht, J.C.; de Valk, H.W.; Sales, L.A.; Parrot-Rouland, F.M.;
Tan, K.S.; Higgins, I.; Garcon, D. and Andria, G. (1997) JAMA,
277(22), 1775-1781.
[39] Verhoef, P.; Meleady, R.; Daly, L.E.; Graham, I.M.; Robinson, K.
and Boers, G.H. (1999) Eur. Heart J., 20(17), 1234-1244.
[40] Kutzbach, C. and Stokstad, E.L. (1971) Biochim. Biophys Acta,
250(3), 459-477.
[41] Matthews, A.; Johnson, T.N.; Rostami-Hodjegan, A.; Chakrapani,
A.; Wraith, J.E.; Moat, S.J.; Bonham, J.R. and Tucker, G.T. (2002)
Br. J. Clin. Pharmacol., 54(2), 140-146.
[42] Schwahn, B.C.; Hafner, D.; Hohlfeld, T.; Balkenhol, N.; Laryea,
M.D. and Wendel, U. (2003) Br. J. Clin. Pharmacol., 55(1), 6-13.
[43] Mudd, S.H.; Ebert, M.H. and Scriver, C.R. (1980) Metabolism,
29(8), 707-720.
[44] Mudd, S.H. and Poole, J.R. (1975) Metabolism, 24(6), 721-735.
[45] Zeisel, S.H.; Da Costa, K.A.; Franklin, P.D.; Alexander, E.A.;
Lamont, J.T.; Sheard, N.F. and Beiser, A. (1991) FASEB J., 5(7),
[46] Buchman, A.L.; Dubin, M.; Jenden, D.; Moukarzel, A.; Roch,
M.H.; Rice, K.; Gornbein, J.; Ament, M.E. and Eckhert, C.D.
(1992) Gastroenterology, 102(4 Pt 1), 1363-1370.
[47] Sugiyama, K.; Mochizuki, C. and Muramatsu, K. (1987) J. Nutr.
Sci. Vitaminol., (Tokyo), 33(5), 369-376.
22 Current Drug Metabolism, 2005, Vol. 6, No. 1 Olthof and Verhoef
[48] Olson, R.E.; Jablonski, J.R. and Taylor, E. (1958) Am. J. Clin.
Nutr., 6(2), 111-118.
[49] Yao, Z.M. and Vance, D.E. (1988) J. Biol. Chem., 263(6), 2998-
[50] Hayes, K.C.; Pronczuk, A.; Cook, M.W. and Robbins, M.C. (2003)
Food Chem. Toxicol., 41(12), 1685-1700.
[51] Ridgway, N.D. and Vance, D.E. (1988) J. Biol. Chem., 263(32),
[52] Homocysteine Studies Collaboration. (2002) JAMA, 288(16), 2015-
[53] Schnyder, G.; Roffi, M.; Pin, R.; Flammer, Y.; Lange, H.; Eberli,
F.R.; Meier, B.; Turi, Z.G. and Hess, O.M. (2001) N. Engl. J. Med.,
345(22), 1593-1600.
[54] Schnyder, G.; Roffi, M.; Flammer, Y.; Pin, R. and Hess, O.M.
(2002) JAMA, 288(8), 973-979.
[55] Klerk, M.; Verhoef, P.; Clarke, R.; Blom, H.J.; Kok, F.J. and
Schouten, E.G. (2002) JAMA, 288(16), 2023-2031.
[56] Toole, J.F.; Malinow, M.R.; Chambless, L.E.; Spence, J.D.;
Pettigrew, L.C.; Howard, V.J.; Sides, E.G.; Wang, C.H. and
Stampfer, M. (2004) JAMA, 291(5), 565-575.
[57] Clarke, R. and Armitage, J. (2000) Semin. Thromb. Hemost., 26(3),
[58] Chan, S.Y.; Mancini, G.B.; Kuramoto, L.; Schulzer, M.; Frohlich,
J. and Ignaszewski, A. (2003) J. Am. Coll. Cardiol., 42(6), 1037-
[59] Gokce, N.; Keaney, J.F.J.; Hunter, L.M.; Watkins, M.T.;
Menzoian, J.O. and Vita, J.A. (2002) Circulation, 105(13), 1567-
[60] Schachinger, V.; Britten, M.B. and Zeiher, A.M. (2000)
Circulation, 101(16), 1899-1906.
[61] Suwaidi, J.A.; Hamasaki, S.; Higano, S.T.; Nishimura, R.A.;
Holmes, D.R.J. and Lerman, A. (2000) Circulation, 101(9), 948-
[62] Sakamoto, A. and Murata, N. (2002) Plant. Cell Environ., 25(2),
... That's why betaine supplementation can reduce total homocysteine (tHcy) level and they're inversely correlated; therefore betaine used as a treatment for homocysteinemia. (127)(128)(129)(130) Central obesity and excessive flux of fatty acids in the visceral tissue are regarded as the main factors of metabolic syndrome, which leads to insulin resistance and atherogenic dyslipidemia.(131) Betaine intake and plasma levels were inversely correlated with several metabolic syndrome markers. ...
BACKGROUND: Metabolomics is a developed technology that comprehensively analyzes the metabolites in biological specimens. It appears to be a prospective method in the practice of precision medicine.CONTENT: Metabolomic technologies currently surpass beyond the traditional clinical chemistry techniques. Metabolomic is capable to perform a precise analysis for hundreds to thousands of metabolites, therefore provide a detailed characterization of metabolic phenotypes and metabolic derangements that underlie disease, to represent an individual’s overall health status, furthermore to discover new precise therapeutic targets, and discovery of biomarkers, either for diagnosis or therapy monitoring purpose.SUMMARY: Adequate data processing and quantification methods are still needed to be developed to boost integrated -omics as a powerful clinical practice platform.KEYWORDS: metabolomic, precision medicine, phenotyping, biomarker, nutritional pattern
... GABA is another important inhibitory neurotransmitter, and its metabolic changes may be an important factor in neuronal damage caused by cerebral ischemia (Kang et al., 2002), GABA level rises sharply in the early stage of cerebral ischemia injury, causing post-synaptic neurons. Meanwhile, GABA can reduce the release of glutamate through pre-synaptic neurons inhibition, and assist in the transport of Ca 2+ to maintain osmotic pressure inside and outside the cell (Olthof & Verhoef, 2005) to reduce cell damage. Our previous studies have found that ICT protects mice from MCAO/R damage is closely related to the inhibition of brain oxidative stress and neuroinflammation (Sun et al., 2017). ...
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Background Icaritin (ICT) has been previously demonstrated to display protective effects against cerebral ischemic reperfusion (I/R) by inhibiting oxidative stress, but the mechanism remains unclear. This study aimed to explore the mechanism from the perspective of metabolomics. Methods A mice cerebral artery occlusion/reperfusion (MCAO/R) model was explored to mimic cerebral ischemic reperfusion and protective effect of ICT was assessed by neurologic deficit scoring, infarct volume and brain water content. Ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry (UHPLC-ESI-QE-Orbitrap-MS) based metabolomic was performed to explore potential biomarkers. Brain tissue metabolic profiles were analyzed and metabolic biomarkers were identified through multivariate data analysis. The protein levels of Nrf2, HO-1 and HQO1 were assayed by western blot. The release of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were detected using corresponding assay kits. Results The results showed that after ICT treatment, the neurological deficit, cerebral infarction area, brain edema and the level of MDA in brain tissue of MCAO/R mice were significantly reduced. Meanwhile, ICT enhanced the activity of SOD, CAT and GSH-Px. Western blot results confirmed that ICT up-regulated the protein levels of antioxidant-related protein including Nrf2, HO-1 and NQO1. According to the metabolomic profiling of brain tissues, clear separations were observed among the Sham, Model and ICT groups. A total of 44 biomarkers were identified, and the identified biomarkers were mainly related to linoleic acid metabolism, arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, arginine and proline metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism and purine metabolism, respectively. At the same time, the inhibitory effect of ICT on arachidonic acid and linoleic acid in brain tissue, as well as the promoting effect on taurine, GABA, NAAG, may be the key factors for the anti-neurooxidative function of mice after MCAO/R injury. Conclusion Our results demonstrate that ICT has benefits for MCAO/R injury, which are partially related to the suppression of oxidative stress via stimulating the Nrf2 signaling and regulating the production of arachidonic acid, linoleic acid, taurine, GABA, NAAG in brain tissue.
... Betaine acts as a methyl donor for homocysteine remethylation into methionine in the Betaine-Homocysteine Methyltransferase (BHMT)7 reaction. (140) This explains why betaine supplementation reduces plasma Total Homocysteine (tHcy) levels (141) and is inversely linked to plasma betaine levels (142,143). Choline and betaine were shown to have opposite associations with essential metabolic syndrome components, indicating a disturbance of the mitochondrial choline dehydrogenase pathway. ...
BACKGROUND: Metabolism impairment in obese condition usually initially triggered by inflammation and insulin signaling impairment. The involvement of metabolites, including lipids, amino acids, and ketone bodies, in altering insulin sensitivity has been revealed after massive data sets were provided by the studies regarding metabolomics and lipidomics. CONTENT: Metabolites were now understood to serve more than just the metabolism products, but also as active signaling molecules including in insulin and immunological actions. Different lipid metabolites can serve as signaling molecules to induce insulin resistance of sensitivity through a similar pathway, and impact on the inflammation status. Branched Chain Amino Acids (BCAA) and many amino acids have been correlated with mitochondrial dysfunction and insulin impairment. Ketogenic diet, supplementation and microbiota transplantation become the current strategies to set a preferable metabolites composition to modulate insulin sensitivity. SUMMARY: Thousands of metabolites can now be measured using technical and bioinformatics developments. Different types of amino acids, fatty acids, and bile acids are being studied in relation to altered metabolic states, particularly obesity and type 2 diabetes mellitus. A thorough knowledge of the metabolic changes that contribute to insulin resistance might lead to the discovery of new targets for enhancing insulin sensitivity and preventing and treating many metabolic disorders. KEYWORDS: metabolites, insulin resistance, lipids, amino acids, ketone bodies
... Homocystinuria Lowers plasma tHcy levels Promotion of methionine-homocysteine cycle Craig (2004) Cardiovascular disease Lowers plasma tHcy levels Promotion of methionine-homocysteine cycle Schwab et al. (2006) Frontiers in Molecular Biosciences (Olthof and Verhoef, 2005). Methionine-loading test is used as an indicator of the propensity of the individual to heart disease (Garlick, 2006). ...
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Osmolytes are naturally occurring small molecular weight organic molecules, which are accumulated in large amounts in all life forms to maintain the stability of cellular proteins and hence preserve their functions during adverse environmental conditions. Trimethylamine N-oxide (TMAO) and N,N,N-trimethylglycine (betaine) are methylamine osmolytes that have been extensively studied for their diverse roles in humans and have demonstrated opposing relations with human health. These osmolytes are obtained from food and synthesized endogenously using dietary constituents like choline and carnitine. Especially, gut microbiota plays a vital role in TMAO synthesis and contributes significantly to plasma TMAO levels. The elevated plasma TMAO has been reported to be correlated with the pathogenesis of numerous human diseases, including cardiovascular disease, heart failure, kidney diseases, metabolic syndrome, etc.; Hence, TMAO has been recognized as a novel biomarker for the detection/prediction of several human diseases. In contrast, betaine acts as a methyl donor in one-carbon metabolism, maintains cellular S-adenosylmethionine levels, and protects the cells from the harmful effects of increased plasma homocysteine. Betaine also demonstrates antioxidant and anti-inflammatory activities and has a promising therapeutic value in several human diseases, including homocystinuria and fatty liver disease. The present review examines the multifarious functions of TMAO and betaine with possible molecular mechanisms towards a better understanding of their emerging and diverging functions with probable implications in the prevention, diagnosis, and treatment of human diseases.
... In addition, higher PEPs have been associated with a lower quality diet, 62-65 characterized by fewer folate sources; lower folate intake may lead to higher homocysteine levels, which has been observed in XFS. 20,21,66 Although we observed nonsignificant modest positive associations with homocysteine itself, given that other metabolites such as lower phosphatidylcholines, 67 lower betaine, 68 and higher levels of coffee-related metabolites (i.e., 3methylxanthine and trigonelline) 69,70 that increase homocysteine were near significant, the homocysteine pathway may be relevant in the disease process. ...
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Purpose: The etiology of exfoliation glaucoma (XFG) is poorly understood. We aimed to identify a prediagnostic plasma metabolomic signature associated with XFG. Methods: We conducted a 1:1 matched case-control study nested within the Nurses' Health Study and Health Professionals Follow-up Study. We collected blood samples in 1989-1990 (Nurses' Health Study) and 1993-1995 (Health Professionals Follow-up Study). We identified 205 incident XFG cases through 2016 (average time to diagnosis from blood draw = 11.8 years) who self-reported glaucoma and were confirmed as XFG cases with medical records. We profiled plasma metabolites using liquid chromatography-mass spectrometry. We evaluated 379 known metabolites (transformed for normality using probit scores) using multiple conditional logistic models. Metabolite set enrichment analysis was used to identify metabolite classes associated with XFG. To adjust for multiple comparisons, we used number of effective tests (NEF) and the false discovery rate (FDR). Results: Mean age of cases (n = 205) at diagnosis was 71 years; 85% were women and more than 99% were Caucasian; controls (n = 205) reported eye examinations as of the matched cases' index date. Thirty-three metabolites were nominally significantly associated with XFG (P < 0.05), and 4 metabolite classes were FDR-significantly associated. We observed positive associations for lysophosphatidylcholines (FDR = 0.02) and phosphatidylethanolamine plasmalogens (FDR = 0.004) and inverse associations for triacylglycerols (FDR < 0.0001) and steroids (FDR = 0.03). In particular, the multivariable-adjusted odds ratio with each 1 standard deviation higher plasma cortisone levels was 0.49 (95% confidence interval, 0.32-0.74; NEF = 0.05). Conclusions: In plasma from a decade before diagnosis, lysophosphatidylcholines and phosphatidylethanolamine plasmalogens were positively associated and triacylglycerols and steroids (e.g., cortisone) were inversely associated with XFG risk.
... Betaine donates a methyl group to methylate phosphatidylethanolamine, forming phosphatidylcholine [48]. Studies have indicated that betaine supplementation improves the blood lipid profile [49,50] by increasing phosphatidylcholine synthesis and enhancing lipid transportation from the liver to the blood [51]. Moreover, because betaine is produced by the irreversible oxidation of choline, betaine supplementation does not deplete choline levels, resulting in the higher synthesis of phosphatidylcholine in the liver [20]. ...
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The purpose of this study was to investigate the effects of 6-week betaine supplementation during a preparatory period of collegiate athletes on muscular power and strength. Sixteen male collegiate athletes received 5 g/day of betaine (betaine group, n = 9) or carboxymethyl cellulose (placebo group, n = 7) for 6 weeks. All participants engaged in their regular training during the experimental period. The overhead medicine-ball throw (OMBT), countermovement jump, and maximal strength (one repetition maximum, 1-RM) on the bench press, overhead press, half squat, and sumo dead lift by the participants were assessed before and after betaine supplementation. Blood lipids were also analyzed before and after betaine supplementation. After supplementation, there were no significant differences between betaine and placebo groups on any variables. Compared to presupplementation, the performance of OMBT and 1-RM of overhead press and half squat in the betaine group had significantly improved (p < 0.05). By contrast, no significant differences were observed in the placebo group before and after supplementation. Blood analysis revealed no negative effect on blood lipid profiles. Betaine seems to be a useful nutritional strategy to improve and maintain performance during 6-week preparatory periods in collegiate athletes.
... Both of these betalains have been demonstrated to exhibit antioxidant and anti-inflammatory characteristics (Tang et al., 2015b). Choline and betaine, as well as the precursor of betaine, are both used in the treatment of diabetes, in addition to obesity and other chronic disease (Olthof and Verhoef, 2005). Tannins and flavonol glycosides have antiviral, antiinflammatory, antimicrobial, antioxidant, and carcinogenic effects (Jarvis et al., 2017). ...
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Quinoa (Chenopodium quinoa Willd.) is acknowledged as golden grains, is widely regarded as a multipurpose crop. The nutritional and health benefits of quinoa have made it a popular food around the world in the last decade. It is a nutrient-rich pseudo-cereal crop that has been introduced in Pakistan in the recent past, because of its medicinal, commercial value. The plant contains huge number of phytochemicals i.e. amino acids, fiber, minerals, vitamins, secondary metabolites, bioactive proteins and peptides which could be used in various medicine for human and other animal's health. It has been reported that the quinoa leaves, root, and seed are used in the treatment of diabetes, cancer, inflammations, fungal infections, and other numerous health problems. In addition, its high energy, nutrient content, therapeutic properties, and lack of gluten, it is considered to be useful for children, the elder, lactose-intolerant people, and osteoporosis in women. Besides, it is considered a crop oil, because the seed oil fractions are extremely nutrient-dense and can be used in skin care, cosmetics, and as a raw material for other products. This comprehensive study provides medical uses, phytochemical constituents, and pharmacological activities of quinoa. Also, the anti-inflammatory, antimicrobial, antidiabetic, antioxidant, antitumor, antilipidemic, antibacterial, and antifungal effects have been reviewed. This review is providing the detail study about the phytochemicals and pharmacological evaluation of quinoa till date, and also provides pave for future investigations and exploitation of C. quinoa.
... The half-life increases with increasing dosage and supplementation time, while absorption remains unchanged [33]. Under normal conditions, with basal renal osmolyte concentrations, the serum concentration of betaine in humans is 10-50 mmol/L [31,34]. The current intake recommendation for betaine to show its positive effects is 1500 mg/day as per the literature survey. ...
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Purpose of Review This narrative review aimed to explore the functions of betaine and discuss its role in patients with chronic kidney disease (CKD). Recent Findings Some studies on CKD animal models have shown the benefits of betaine supplementation, including decreased kidney damage, antioxidant recovery status, and decreased inflammation. Summary Betaine (N-trimethylglycine) is an N-trimethylated amino acid with an essential regulatory osmotic function. Moreover, it is a methyl donor and has anti-inflammatory and antioxidant properties. Additionally, betaine has positive effects on intestinal health by regulating the osmolality and gut microbiota. Due to these crucial functions, betaine has been studied in several diseases, including CKD, in which betaine plasma levels decline with the progression of the disease. Low betaine levels are linked to increased kidney damage, inflammation, oxidative stress, and intestinal dysbiosis. Furthermore, betaine is considered an essential metabolite for identifying CKD stages.
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Acute kidney injury (AKI) is common in critically ill patients, and sepsis is its leading cause. Sepsis-associated AKI (SA-AKI) causes greater morbidity and mortality than other AKI etiologies, yet underlying mechanisms are incompletely understood. Metabolomic technologies can characterize cellular energy derangements, but few discovery analyses have evaluated the metabolomic profile of SA-AKI. To identify metabolic derangements amenable to therapeutic intervention, we assessed plasma and urine metabolites in septic mice and critically ill children and compared them by AKI status. Metabolites related to choline and central carbon metabolism were differentially abundant in SA-AKI in both mice and humans. Gene expression of enzymes related to choline metabolism were altered in the kidneys and liver of mice with SA-AKI. Treatment with intraperitoneal choline improved renal function in septic mice. Because septic pediatric patients displayed similar metabolomic profiles to septic mice, choline supplementation may attenuate pediatric septic AKI.
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Background This study aimed to evaluate the association between homocysteine-related dietary patterns and gestational diabetes mellitus. Methods A total of 488 pregnant women at 24–28 weeks of gestation between January 2019 and December 2020 were included. Demographic characteristics, dietary intake, and multivitamin supplement intake information were collected using a food frequency questionnaire (FFQ); fasting venous blood samples were collected for serum index detection. Serum homocysteine (Hcy), folic acid, and B12 were selected as response variables, and hyperhomocysteinemia (hHcy)-related dietary patterns were extracted using the reduced rank regression.. The relationship between the score of hHcy-related dietary patterns and GDM was analyzed using a multivariate logistic regression model. Results Three hHcy-related dietary patterns were extracted. Only mode 2 had a positive and significant relationship with the risk of developing GDM. After adjusting for confounding factors, the risk of GDM was significantly increased in the highest quartile array compared with the lowest quartile of the pattern (OR = 2.96, 95% Confidence Interval : 0.939–9.356, P = 0.004). There was no significant correlation between dietary pattern 1 and GDM risk ( P > 0.05). Conclusions Homocysteine-related dietary patterns were positively associated with gestational diabetes mellitus. Adjusting dietary patterns may contribute to the intervention and prevention of GDM.
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Context In observational studies, individuals with elevated levels of plasma homocysteine tend to have moderately increased risk of coronary heart disease (CHD). The MTHFR 677C→T polymorphism is a genetic alteration in an enzyme involved in folate metabolism that causes elevated homocysteine concentrations, but its relevance to risk of CHD is uncertain.Objective To assess the relation of MTHFR 677C→T polymorphism and risk of CHD by conducting a meta-analysis of individual participant data from all case-control observational studies with data on this polymorphism and risk of CHD.Data Sources Studies were identified by searches of the electronic literature (MEDLINE and Current Contents) for relevant reports published before June 2001 (using the search terms MTHFR and coronary heart disease), hand searches of reference lists of original studies and review articles (including meta-analyses) on this topic, and contact with investigators in the field.Study Selection Studies were included if they had data on the MTHFR 677C→T genotype and a case-control design (retrospective or nested case-control) and involved CHD as an end point. Data were obtained from 40 (34 published and 6 unpublished) observational studies involving a total of 11 162 cases and 12 758 controls.Data Extraction Data were collected on MTHFR 677C→T genotype, case-control status, and plasma levels of homocysteine, folate, and other cardiovascular risk factors. Data were checked for consistency with the published article or with information provided by the investigators and converted into a standard format for incorporation into a central database. Combined odds ratios (ORs) for the association between the MTHFR 677C→T polymorphism and CHD were assessed by logistic regression.Data Synthesis Individuals with the MTHFR 677 TT genotype had a 16% (OR, 1.16; 95% confidence interval [CI], 1.05-1.28) higher odds of CHD compared with individuals with the CC genotype. There was significant heterogeneity between the results obtained in European populations (OR, 1.14; 95% CI, 1.01-1.28) compared with North American populations (OR, 0.87; 95% CI, 0.73-1.05), which might largely be explained by interaction between the MTHFR 677C→T polymorphism and folate status.Conclusions Individuals with the MTHFR 677 TT genotype had a significantly higher risk of CHD, particularly in the setting of low folate status. These results support the hypothesis that impaired folate metabolism, resulting in high homocysteine levels, is causally related to increased risk of CHD. Figures in this Article Homocysteine is a sulfur-containing amino acid that plays a pivotal role in methionine metabolism. Genetic defects of the enzymes or dietary deficiency of B-vitamin cofactors involved in this metabolism result in elevated homocysteine levels. Elevated homocysteine levels have been associated with increased risk of coronary heart disease (CHD),1 but whether this association is causal is uncertain.2 Observational studies have shown that individuals with low folate levels or intake have a higher risk of CHD,3- 6 and it is possible that these associations may be independent of homocysteine.7 A common polymorphism exists for the gene that encodes the methylene tetrahydrofolate reductase (MTHFR) enzyme, which converts 5,10-methylene tetrahydrofolate to 5-methyltetrahydrofolate, required for the conversion of homocysteine to methionine. Individuals who have a C-to-T substitution at base 677 of the gene (amino acid change A222V) have reduced enzyme activity and higher homocysteine8 and lower folate levels than those without this substitution.9- 13 Elucidation of an association, if any, between this polymorphism and CHD risk might be informative regarding the hypothesis that impaired folate metabolism, resulting in high homocysteine concentrations, plays a causal role in the occurrence of CHD. Individual studies and previous meta-analyses of such studies8,14 included too few subjects to provide conclusive evidence for or against an association of this polymorphism and CHD risk.15 The aim of this study was to assess the relation of the MTHFR 677C→T polymorphism with risk of CHD by conducting a meta-analysis of individual participant data from all case-control observational studies that had data on this polymorphism and risk of CHD.
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Choline is required to make essential membrane phospholipids. It is a precursor for the biosynthesis of the neurotransmitter acetylcholine and also is an important source of labile methyl groups. Mammals fed a choline-deficient diet develop liver dysfunction; however, choline is not considered an essential nutrient in humans. Healthy male volunteers were hospitalized and fed a semisynthetic diet devoid of choline supplemented with 500 mg/day choline for 1 wk. Subjects were randomly divided into two groups, one that continued to receive choline (control), and the other that received no choline (deficient) for three additional wk. During the 5th wk of the study all subjects received choline. The semisynthetic diet contained adequate, but no excess, methionine. In the choline-deficient group, plasma choline and phosphatidylcholine concentrations decreased an average of 30% during the 3-wk period when a choline-deficient diet was ingested; plasma and erthrocyte phosphatidylcholine decreased 15%; no such changes occurred in the control group. In the choline-deficient group, serum alanine aminotransferase activity increased steadily from a mean of 0.42 mukat/liter to a mean of 0.62 mukat/liter during the 3-wk period when a choline-deficient diet was ingested; no such change occurred in the control group. Other tests of liver and renal function were unchanged in both groups during the study. Serum cholesterol decreased an average of 15% in the deficient group and did not change in the control group. Healthy humans consuming a choline-deficient diet for 3 wk had depleted stores of choline in tissues and developed signs of incipient liver dysfunction. Our observations support the conclusion and choline is an essential nutrient for humans when excess methionine and folate are not available in the diet.
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We conducted a systematic evaluation of the effects of increasing levels of dietary methionine on the metabolites and enzymes of methionine metabolism in rat liver. Significant decreases in hepatic concentrations of betaine and serine occurred when the dietary methionine was raised from 0.3 to 1.0%. We observed increased concentrations of S-adenosylhomocysteine in livers of rats fed 1.5% methionine and of S-adenosylmethionine and methionine only when the diet contained 3.0% methionine. Methionine supplementation resulted in decreased hepatic levels of methyltetrahydrofolate-homocysteine methyltransferase and increased levels of methionine adenosyltransferase, betaine-homocysteine methyltransferase, and cystathionine synthase. We used these data to simulate the regulatory locus formed by the enzymes which metabolize homocysteine in livers of rats fed 0.3% methionine, 1.5% methionine, and 3.0% methionine. In comparison to the model for the 0.3% methionine diet group, the model for the 3.0% methionine animals demonstrates a 12-fold increase in the synthesis of cystathionine, a 150% increase in flow through the betaine reaction, and a 550% increase in total metabolism of homocysteine. The concentrations of substrates and other metabolites are significant determinants of this apparent adaptation.
Plasma-free choline levels have previously been found below normal in patients receiving long term parenteral nutrition (TPN). In a group of 15 patients receiving home TPN who had low plasma free choline levels (6.3 +/- 0.8 mmol/L), we found 50% had hepatic steatosis. These patients were given oral lecithin or placebo in a double-blind randomized trial for 6 weeks. Lecithin supplementation led to an increase in plasma free choline of 53.4% +/- 15.4% at 2 weeks (P = 0.04), which continued at 6 weeks. The placebo group had no change in plasma-free choline at 2 weeks, but a significant decrease of 25.4% +/- 7.1% (P = 0.01) at 6 weeks. A significant and progressive decrease in hepatic fat was indicated by increased liver-spleen CT Hounsfield units at 2 and 6 weeks (7.5 +/- 1.7 units, P = 0.02; 13.8 +/- 3.5 units, P = 0.03) in the lecithin supplemental group. Nonsignificant changes were seen in the placebo group. It was concluded that hepatic steatosis in many patients receiving long term TPN is caused by plasma-free choline deficiency and may be reversed with lecithin supplementation. Choline is a conditionally essential nutrient in this population. (Gastroenterology 1992 Apr;102(4 Pt 1):1363-70)
Oral anhydrous betaine was administered, along with an unrestricted diet, to two presumably cystathionine-synthase-deficient pyridoxine-nonresponsive patients with homocystinuria. Betaine treatment resulted in a significant decrease (to 1/4 of control) in plasma homocystine concentration and a rise (two- to four-fold) in plasma methionine values. This biochemical response was accompanied by clinical improvement. There were no apparent ill effects after more than two years of betaine supplementation.
Estimates of the daily rate of methionine utilization by adult humans, published previously, were under-estimated because available data did not permit quantitative assessment of the rate at which the methyl moiety of methionine is oxidized.1 The present paper reports efforts to measure the rate of oxidation of methionine methyl by the two pathways that proceed through the intermediate N-methylglycine (sarcosine). Two sarcosinemic, sarcosinuric patients, proven or presumed to have specific genetic defects in the sarcosine-oxidizing system, were studied while maintained on constant diets containing differing amounts of methionine, choline (or choline derivatives), and glycine. The steadystate excretions of sarcosine, creatinine, creatine, and a number of other materials were determined. The results obtained suggest that sarcosine is formed in 2 ways: (1) In an amount equivalent to the dietary intake of choline (or choline derivative)—this pathway would make a net positive contribution to the methionine-methyl pool due to the transfer of a methyl group from betaine to homocysteine; and (2) By processes requiring net consumption of methionine methyl. For the single patient for whom reasonably complete data were attained, it appears that 2 such processes may be occurring. One proceeds at a rate (approximately 2 mmole/24 hr) that changed little as total intake of labile methyl groups∗ was altered. The second became prominent (and accounted for the bulk of the incremental intake of labile methyl groups) when this intake exceeded the combined amounts required for the synthesis of creatine (10.2 mmole/24 hr), other transmethylation reactions (1.4 mmole/24 hr), polyamine synthesis (0.5 mmole/24 hr), and the “basal” process of sarcosine formation just mentioned (2 mmole/24 hr). It is possible that such “basal” sarcosine formation is due chiefly to endogenous choline synthesis, balanced by degradation, whereas the more responsive process of sarcosine formation may be due chiefly to methylation of glycine. Together with available data, these new data on methionine consumption due to sarcosine formation permit calculation of a turnover time for S-adenosylmethionine in human liver (no more than 3.5–7 min), as well as upward revision of previous minimal estimates1 of the rate of methylneogenesis, the number of times that the average homocysteinyl moiety cycles between methionine and homocysteine during its passage through the body, and the partitioning of homocysteine between the remethylation and the transsulfuration pathways.
In France, a diet high in saturated fat and cholesterol is associated with low coronary artery disease mortality and it may be that drinking wine is protective against ischemic heart disease. Recent studies suggest that high plasma homocysteine concentrations are an independent risk factor for coronary, cerebral and peripheral arterial occlusive diseases. One of several routes for metabolism of homocysteine involves methylation using betaine as the methyl donor. Betaine is often added to less expensive wine when beet sugar is used to increase alcohol content. We found that many commercial wines contain betaine; an average glass of wine contains approximately 3 mg betaine. This small amount is less than the dose used to lower homocysteine in patients with genetic forms of hyperhomocysteinemia, but we do not know whether humans with modest elevations of homocysteine would be influenced by this dose.
Normal young adult male and female subjects were maintained on fixed dietary regimens which were either essentially normal or were semisynthetic and curtailed in methionine and choline intakes and virtually free of cystine. The subjects maintained stable weights and remained in positive nitrogen balance or within the zone of sulfur equilibrium. Choline intakes were calculated, and urinary excretions of creatinine, creatine, and sacrosine were measured. Creatinine excretions of male subjects on essentially normal diets outweighed the total intakes of labile methyl groups. Taking into account the excretions of additional methylated compounds, as judged from published values, it appears that methyl neogenesis must normally play a role in both males and females. When labile methyl intake is curtailed, de novo formation of methyl groups is quantitatively more significant than ingestion of preformed methyl moieties. On the normal diets used in these experiments, the average homocysteinyl moiety in males cycled between methionine and homocysteine at least 1.9 times before being converted to cystathionine. For females, the average number of cycles was at least 1.5. When labile methyl intake was curtailed, the average number of cycles rose to 3.9 for males and 3.0 for females under the conditions employed.
We examined the effects of feeding rats a choline deficient diet, of treating rats with low doses of methotrexate (MTX, 0.1 mg/kg, daily), and of combined choline deficiency and MTX treatment upon the content and distribution of folates in liver. We used a newly devised technique for analysis of folates which utilized affinity chromatography followed by high pressure liquid chromatography. Compared to control rats, total hepatic folate content decreased by 31% in the choline deficient rats, by 48% in the MTX treated rats, and by 60% in rats which were both choline deficient and treated with MTX. In extracts of livers from control rats, folates were present predominantly as penta (35%) and hexaglutamyl (52%) derivatives. The pteridine ring structure distribution of these folates was as follows: 48% 5-methyltetrahydrofolate, 14% formylated tetrahydrofolate, and 39% tetrahydrofolate. In choline deficient animals, there was a decrease in the relative concentration of pentaglutamyl folates and an increase in the relative concentration of heptaglutamyl folates. In livers from MTX treated animals, MTX-polyglutamates with 2-5 glutamate residues accumulated. The consequences of MTX treatment were: a) an elongation of the glutamate chains of the folates as the proportion of hepta- and octaglutamyl derivatives was increased relative to penta- and hexaglutamyl folates; b) the occurrence of unreduced folic acid; c) a decrease in the relative concentration of 5-methyltetrahydrofolate and an increase in the relative concentration of formylated tetrahydrofolate, and d) no change in the relative concentrations of tetrahydrofolate. In livers from animals that were both choline deficient and treated with MTX, the tetrahydrofolate concentrations were 50% of control while formylated tetrahydrofolate concentrations increased 3-fold. These data are discussed from the standpoint of the current understanding of mechanisms that regulate the elongation of the glutamic acid chains of folates and those that regulate folate dependent synthesis and utilization of one carbon unit.