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* Western Human Nutrition Research Center, U.S. Department of Agriculture, Agricultural Research Service, Presidio of San Francisco, CA 94129;
Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90024;
** Department of Biochemistry, University of Sydney, NSW, 2006, Australia and
School of Public Health, University of California, Los Angeles, CA 90024
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • Choline • folic acid • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Choline is a methyl-rich compound required for
phospholipid synthesis and neurotransmitter function (Zeisel 1994
). The two compounds are closely related in the reactions
of the methyl cycle, as shown in Fig. 1
. Either 5-methyltetrahydrofolate or betaine, an oxidized form of
choline, can supply methyl groups to methylate homocysteine to
methionine. Methionine is then converted to S-adenosylmethionine
(SAM),5
the methyl donor for many biological methylation reactions. The latter
include the sequential addition of three methyl groups to
phosphatidylethanolamine to form phosphatidylcholine.
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, Varela-Moreiras et al. 1992 and 1995
). Hepatic folate depletion, DNA hypomethylation, and
increased plasma homocysteine due to choline depletion were reversed
within 2 wk by adding adequate dietary choline (Varela-Moreiras et al. 1995
).
Decreased hepatic betaine and increased betaine:homocysteine
methyltransferase activity in rats made folate deficient or treated
with folate antagonists indicate that choline is utilized to methylate
homocysteine when the availability of methylfolate is limited
(Barak and Kemmy 1982
, Barak et al. 1984
,
Finkelstein and Martin 1984
, Trimble et al. 1993
). Rats made severely folate deficient had 65 and 80%
lower hepatic choline and phosphocholine levels than did folate
adequate controls, and moderately folate deficient rats had a 36%
(P < 0.09) reduction in hepatic choline (Kim et al. 1994
).
Traditionally, choline has not been classified as an essential dietary
nutrient because phosphatidylcholine can be synthesized de novo from
phosphatidylethanolamine by the reaction shown in Fig. 1
. This reaction
is catalyzed by phosphatidylethanolamine-N-methyltransferase (EC
2.1.1.17) and occurs in many tissues but predominately in the liver
(Zeisel 1994
). Also, as seen in Fig. 1
, the availability
of SAM for de novo biosynthesis of phosphatidylcholine is dependent on
a supply of the essential nutrients methionine, folate, and vitamin
B-12.
In an experimental choline depletion/repletion study, Zeisel et al. (1991)
found that feeding healthy men a choline-deficient
diet with adequate methionine and folate for 3 wk resulted in low
plasma choline and phosphatidylcholine and liver dysfunction, all of
which were reversed upon choline repletion. The authors concluded that
choline is an essential nutrient for humans when sufficient methionine
and folate are not available in the diet. Patients receiving total
parenteral nutrition solutions with adequate folate and methionine but
no choline develop low plasma choline levels and fatty liver, a sign of
functional choline deficiency (Buchman et al. 1995
).
These effects were reversed with intravenous choline chloride
supplementation of 1–4 g/d for 6 wk. These human studies indicate that
plasma choline and phosphatidylcholine are markers of choline
deficiency.
The recent report of Dietary Reference Intakes for B vitamins provides
an estimated Adequate Intake for choline of 425 and 550 mg/d for adult
women and men, respectively (Food and Nutrition Board
1998
). This is based on evidence that de novo synthesis of
choline is not always sufficient to meet human requirements and that
insufficient data are available to calculate a recommended dietary
allowance (RDA).
The rat studies noted above suggest that the human dietary requirement for choline may depend on co-existing folate nutriture. Because this relationship has not been studied in humans, we measured, and report here, the effect of controlled folate depletion and repletion on the choline status of healthy men and women fed low-choline diets.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Choline data are reported for men and women from two studies carried out on the USDA Western Human Nutrition Research Center's (WHNRC) metabolic unit in 1990 (men) and 1995 (women). The study protocols and informed consents were approved by the Human Subjects Review Committees of the Letterman Army Medical Center, Presidio of San Francisco, CA (men's study); the University of California, Davis (women's study); and the Agricultural Research Service, U.S. Department of Agriculture (both studies). Signed informed consent was obtained from each volunteer after having read the protocol and discussed the study's purpose, procedures, risks, and benefits.
Volunteer participants were admitted to the studies after medical and psychological screening that included medical histories, physical and dental examinations, hematological and clinical chemistry tests, psychological testing, resting electrocardiogram, and tests for hepatitis, syphilis, tuberculosis, and HIV-antibodies. Tests for alcohol, tobacco, and drug use were also performed. For the duration of the studies, the subjects lived and ate all meals in the WHNRC metabolic unit and were chaperoned at all times when outside the unit.
Men.
Twelve healthy nonsmoking male volunteer subjects, ages 33–46 y,
within 90–120% of desirable body weight were enrolled (Jacob et al. 1994
). Data reported here are for 11 men because one
subject left the study early on d 40. The study lasted 108 d.
Women.
Ten healthy nonsmoking postmenopausal women, ages 49–63 y, were
enrolled (Jacob et al. 1998
). Additional screening
criteria for the women volunteers included negative human papilloma
virus (PAP smear), non-use of vitamin or health food supplements
containing folic acid, hemoglobin > 115 g/L, and hematocrit > 0.34. All women were within 90–130% of desirable weight, except
for one subject who was 145% of desirable weight. Three subjects on
estrogen replacement therapy before entering the study continued the
same regimen throughout. The study lasted 91 d.
Experimental design and diet.
As detailed below, the study designs and diets were different for the
men's and women's studies; however, the following aspects were common
to both studies. During folate-depletion periods, subjects consumed
low-folate/low-choline diets for 4–5 wk followed by a 2–6-wk folate
repletion period, when varying amounts of synthetic folic acid
(pteroylglutamic acid) were added to the diet. The diets were designed
to limit choline intake as an exogenous methyl group source.
Crystalline amino acids were supplemented into the diet to meet the
requirements for nitrogen balance. Vitamins and minerals were provided
as supplements to meet the RDA (National Research Council 1989
) for most micronutrients and to exceed the RDA for the B
vitamins involved in methyl group metabolism, vitamins B-2, B-6, and
B-12. Supplements provided 100% of the RDA for vitamins B-2, B-6, and
B-12 in the men's study (Jacob et al. 1994
) and 200%,
234%, and 124% of the RDA, respectively, in the women's study
(Jacob et al. 1998
). Subjects were given free access to
water, salt, non-caloric sweetener, diet soft drinks, and instant
coffee. Consumption of tea and pepper was prohibited, as was smoking,
alcoholic beverages, and drugs, except for those approved for medical
use. All subjects took 1 or 2 chaperoned walks each day totaling
3.2–6.4 km/d.
The length of metabolic periods and total folate intakes are shown in
Table 1
and Figures 2–5
(because choline status did not change during the first half of the
men's study, only results for the second half are shown in Table 1
).
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, each half consisted of three folate intake periods: a 9-d
baseline period in which subjects consumed a repeating 1-d menu of
typical Western foods that provided 440 µg/d of folate and two
low-folate periods in which subjects consumed a low folate diet that
provided 25 µg/d for 30 d and 99 µg/d for 15 d.
Additional folate was supplemented into the low folate diet by adding a
known volume of a pteroylglutamic acid (Sigma Chemical Co., St. Louis
MO) solution in 0.1 mol sodium bicarbonate/L to a soybean shake
consumed with each lunch. As calculated from food composition tables
(USDA 1989
) the one-day baseline menu, at 11.30 MJ (2700
kcal), provided 54% of energy from carbohydrates, 38% from fat, 8%
from protein, and 440 µg/d of folate. The low-folate diet was a 3-d
repeating menu of meatless foods in which nitrogen was supplied from a
low methionine soybean protein isolate and a mixture of purified amino
acids with methionine and cysteine omitted. At a daily energy level of
11.30 MJ, the low-folate diet provided 66% of energy from
carbohydrates, 26% from fat, 8% from protein, and an estimated 25
µg/d of folate. Analysis of the 3 daily diet composites for the
low-folate menus gave a value of <50 µg/d of folate, the lower limit
of detection by the Lactobacillus casei microbiological
assay method of Hurdle et al. (1968)
. The average total
choline contents of the diets (as choline chloride), determined by a
gas chromatography-mass spectrometry procedure (Freeman et al.
1975
), were 239 mg/d and 238 mg/d for the baseline and
low-folate diets, respectively. A detailed description of the baseline
and low folate diets, and dietary supplements, is given in a prior
report (Jacob et al. 1994
). The men's body weights were measured daily, and adjustments in energy intakes (range: 9.63–13.40 MJ/d) were made if subjects deviated beyond ±2% of the baseline weight, taken as the average weight over Days 5–8. Body weights ranged from 63.6 to 85.8 kg and declined an average of 3.1% (mean: 74.1–71.8 kg) from baseline to the end of the study.
Women.
Subjects consumed a low-folate diet in a 4-d menu rotation for the
entire 91 d. The diet provided an average of 56 µg/d of folate,
and varying amounts of synthetic folic acid (pteroylglutamic acid) were
added into the diet to provide folate intake periods of 56 to 516
µg/d as shown in Table 1
and Fig. 4
. A full description of the low
folate diet, and dietary supplements, is given in a prior report
(Jacob et al. 1998
). The diet contained low-protein
bread, pasta and crackers; olive oil; soy margarine; meats (chicken,
turkey, and ham); and fruits and vegetables (applesauce, stewed
tomatoes, carrots, green beans, zucchini squash, pears, dried apricots,
and prunes). Five foods (green beans, carrots, chicken, turkey, and
ham) were boiled three times for 7 min each, and the water discarded to
lower their folate content by ~50%.
Folic acid was added into the diet by mixing a weighed aliquot of folic
acid supplement solution (U.S.P. folic acid, Hoffmann-La Roche,
Belvidere, NJ) into the applesauce served at each breakfast and dinner.
Folic acid concentrations of the supplement solutions were calculated
gravimetrically and checked spectrophotometrically at 282 nm using a
molar extinction coefficient of 27,600 L/(mol · cm) (Blakley 1969
). As calculated from food composition tables (USDA
1991
), the low folate diet at 8.79 MJ (2100 kcal) provided 61%
of energy from carbohydrate, 9.6% from protein, and 29.4% from fat.
Of 50 g/d of protein intake, 35 g came from the diet and 15 g
protein equivalents from crystalline amino acids (18 g amino acids/d).
The diet provided a daily average of 780 mg of methionine and 420 mg of
cysteine, 132% of the estimated 910 mg/d adult requirement for
met + cys (National Research Council 1989
).
Composites of each of the four daily menus used throughout the study
were prepared for determination of folate and choline by blending the
total day's food with an equal volume of cold 0.1 mol potassium
phosphate buffer/L (pH 6.3) containing 57 mmol ascorbic acid/L to
preserve the folate. The food composites were prepared just as for the
study subjects (including triple boiled foods) except foods known to
contain no appreciable folate (soybean margarine, sugar, olive oil,
amino acids, and non-dairy topping) were omitted from the composite.
Aliquots of the four homogenates were analyzed for total folate by
treatment with folate conjugase and microbiological assay using
L. casei as the assay organism (Tamura et al. 1997
). The mean folate content of the four daily menus was 56
µg/d (range: 39–71 µg/d). Use of the newer tri-enzyme technique
(treatment of the homogenate with 
-amylase, protease, and folate
conjugase) resulted in a mean daily folate value of 152 µg/d
(Tamura et al. 1997
). To interpret the results from this
study we use the value of 56 µg/d derived from the traditional assay
method using folate conjugase alone because this allows comparability
to previous reports (Jacob et al. 1994 and 1998
) and the
current RDA for folate.
Separate aliquots of the frozen diet homogenates, prepared as described
above, were analyzed for total choline (free and lipid bound) by a gas
chromatography-mass spectrometry procedure (Freeman et al. 1975
). The choline content of the four daily menus (as choline
chloride) averaged 147 mg/d (range: 132–171 mg/d).
The women's body weights were measured daily, and adjustments in
energy intakes were made if subjects deviated beyond ±5% of the
baseline weight, taken as the average weight over Days 5–7. All food
items were adjusted proportionately when energy intake was changed.
Individual energy intakes ranged from 7.12 to 9.63 MJ/d. Initial body
weights ranged from 55.9 to 93.9 kg and declined an average of 5%
(mean of 69.3–65.7 kg) from Days 5–7 to 91. In addition to chaperoned
walks, the women were allowed to exercise on a voluntary basis 
90
min/wk on the metabolic unit treadmill or stationary bicycle.
Specimen collections and analytical methods.
Fasting blood was taken weekly at 0700–0800 h by venipuncture for
study-related biochemical determinations and for complete blood counts
and clinical chemistry panels to monitor the subjects health (not all
tests were performed weekly). The blood was collected in evacuated
glass tubes and immediately processed for serum, EDTA, heparin, and
citrate plasma. Plasma folate and vitamin B-12 and red cell folate,
(from EDTA anticoagulated blood) were determined by competitive protein
binding radioassay kits (BioRad, Hercules, CA). Plasma and red cell
total choline were determined by a gas chromatography-mass spectrometry
procedure using 2H9-deuterated choline tosylate
as an internal standard (Freeman et al. 1975
).
Phospholipids were extracted from plasma and red cells using 2:1 volume
methanol and chloroform (Folch et al. 1957
) and
separated by unidimensional thin layer chromatography on silica gel HR
plates (Merck, Darmstadt, Germany). The isolated phosphatidylcholine
was visualized with 2',7'-dichlorofluoroscein, scraped into a glass
vial, and quantitated by determination of phosphorus (Bartlett 1959
). Total Hcy was determined in the men's study by
enzymatic conversion of homocysteine to S-adenosylhomocysteine and
determination of S-adenosylhomocysteine by high pressure liquid
chromatography (HPLC) (Henning et al. 1989
), and in the
women's study by HPLC fluorescence detection after derivatization of
homocysteine with a fluorescent sulfonic acid reagent (Araki and Sako 1987
). Erythrocyte SAM was determined using a modification
of an HPLC method for liver tissue analysis (Henning et al. 1989
).
Plasma total cholesterol and triglycerides were determined using
enzymatic assays for the Cobas FARA centrifugal analyzer (Roche,
Nutley, NJ). Serum alanine and aspartate aminotransferases (ALT and
AST, respectively) were determined as part of standard automated
clinical chemistry test panels (Henry et al. 1960
).
Statistics.
Results for plasma and red cell folate, choline, phosphatidylcholine,
and SAM were analyzed for differences caused by dietary folate (and
methionine intake in the men's study). Descriptive statistics were
computed for the end of each folate intake period and are shown as
means ± SEM in Table 1
. Repeated measures ANOVA,
Student-Newman-Keuls, and the Bonferroni multiple-comparison procedures
were used to test for effects of dietary folate intake on folate and
choline status measures (Glantz 1992
). For the men's
study, the effect of different methionine intakes on folate and choline
status measures was determined by a SAS General Linear Models
procedure, which compared the end of the folate depletion and repletion
periods with methionine intake level (400 or 1400 mg/d, respectively).
The statistical analyses were conducted using SAS versions 6.03 and
6.12 (SAS Institute, Cary, NC) and SigmaStat version 1.02 (Jandel
Scientific Software, San Rafael, CA) statistical software programs.
Differences were considered statistically significant at the 0.05
level.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Plasma homocysteine, a functional measure
of folate status, increased during folate depletion (Jacob et al. 1994 and 1998
). Red cell folate and SAM concentrations did
not change significantly, nor did clinical measures of folate
deficiency, including neutrophil segmentation, mean corpuscular volume,
hemoglobin, and hematocrit. All plasma vitamin B-12 concentrations
remained in the normal range throughout. Men.
The two levels of methionine intake had no effect on plasma or red cell
methionine, homocysteine, choline, or SAM. Plasma folate increased
during the low-methionine intakes, likely because of a mobilization of
hepatic folate to the circulating methylfolate form needed for
methionine biosynthesis (Jacob et al. 1994
). Because the
methionine intakes had no effect on choline concentrations, the
subgroups of men getting high or low methionine were combined to
analyze the relationship between folate intake and choline.
Plasma choline concentrations at baseline, end of depletion, and end of
repletion periods are shown for both men and women in Table 1
.
Concentrations of plasma phosphatidylcholine (PC) were obtained for the
men's study only. ANOVA and mutiple-comparison tests showed
significant direct relationships between folate intake and both plasma
choline and PC (Figs. 2–4)
. These relationships were not observed for
the first half of the men's study. Therefore, the mean concentrations
for only the second half of the men's study are shown in Table 1
. Red
cell choline concentrations did not change significantly throughout
either study.
Serum AST values for the men did not change significantly, and all
values (range: 13–55 U/L) remained in the normal range of 0–65 U/L
throughout (Tietz 1995
). Serum triacylglycerols were
unchanged during the first half and decreased significantly in the
second half, from baseline to depletion to repletion (Fig. 5)
. Serum
cholesterol decreased significantly during each depletion period and
remained the same during repletion (Fig. 5)
. Both lipid measures
increased significantly because of the consumption of the higher fat
baseline diet at Days 55–64 (Fig. 5)
.
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Serum transaminases, ALT and AST, were unchanged and remained in the
normal range throughout the study. Means ± SEM values
at baseline, depletion, and repletion for ALT were 10.6 ± 1.3,
11.8 ± 1.1, and 11.8 ± 1.0 U/L, respectively, [normal = 7–35 U/L (Tietz 1995
)] and for AST were 17.6 ±
1.8, 16.2 ± 0.9, and 18.4 ± 1.4 U/L, respectively,
[normal = 8–20 U/L (Tietz 1995
)]. Likewise,
serum triacylglycerols and total cholesterol were unchanged and
remained in the normal range throughout the women's study. Means ± SEM values at baseline, depletion, and repletion for
serum triacylglycerols were 1.11 ± 0.12, 1.13 ± 0.15, and
1.16 ± 0.14 mmol/L, respectively, [normal = 0.6–3.0 mmol/L
(Tietz 1995
)] and for serum total cholesterol were
5.15 ± 0.21, 4.87 ± 0.16, 5.09 ± 0.23 mmol/L,
respectively, [normal = 4.2–7.8 mmol/L (Tietz 1995
)].
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Erythrocyte folate or choline measures
did not change; however, it is likely that the folate intervention
periods were too short to observe changes in tissues and long-lived
cells (Stites et al. 1997
).
Except for the first half of the men's study, significant decreases in
plasma choline and phosphatidylcholine accompanied the folate
depletions, and these decreases were reversed upon folate repletion in
each case. It may be that plasma choline did not change significantly
during the first depletion and repletion periods of the men's study
because hepatic folate and choline stores were adequate to meet the
metabolic needs over the first half of the study despite low folate and
choline intakes (the average dietary choline intake was higher for the
men compared to the women, 238 to 147 mg/d, respectively). Because
choline intake remained constant during the folate repletion periods,
the recovery of choline status can be attributed to the sparing of
choline by the additional folate. Indeed, the data in Table 1
show
that, upon folate repletion, the choline measures returned more fully
to baseline or above than plasma folate and homocysteine. In the men,
the choline measures rebounded even with a marginal folate repletion of
99 µg/d, an amount that was not enough to lower the elevated
homocysteine concentrations in either half of the study (Jacob et al. 1994
). This may reflect a high metabolic priority for
biosynthesis of phosphatidylcholine. The much greater rebound of plasma
choline in the women compared to the men may be caused by their getting
less dietary choline throughout and/or a greater folate repletion, 336
versus 99 µg/d. The possible effects of the age and gender
differences on these pathways are unknown.
The results suggest that the need for choline is significantly
increased during folate deficiency, presumably because of the use of
choline for methyl transfer reactions in the absence of methylfolate.
This is consistent with studies in rats that showed that folate
deficiency resulted in increased hepatic betaine:homocysteine
methyltransferase activity and decreased hepatic betaine and choline
(Kim et al. 1994
, Trimble et al. 1993
).
Increased hepatic betaine:homocysteine methyltransferase activity found
in a patient with reduced 5, 10-methylenetetrahydrofolate reductase
activity suggests that choline-based methylation is upregulated also
during methylfolate deficiency in humans (Freeman et al. 1975
).
A functional consequence of choline deficiency is liver lipid
accumulation and dysfunction caused by the lack of phosphatidylcholine
to mobilize hepatic lipids in the form of lipoproteins (Yao and Vance 1989
). Zeisel et al. (1991)
found that
healthy men fed a choline-deficient diet for 3 wk developed elevated
serum ALT and decreased serum cholesterol. These changes were reversed
upon choline repletion. We found no significant effect of folate and
choline depletion on serum AST or ALT in the men and women of our
studies. Neither were circulating lipids related to choline status. In
the latter half of the men's study, serum lipids were decreased
significantly during the low folate and choline period (Fig. 5)
. This
was likely caused by the transition from the baseline to the low-folate
diet (38 to 26% of energy from fat) because choline measures, but not
serum lipids, increased in the subsequent folate repletion period.
However, because the decline did not occur in the first half, choline
depletion may have contributed to the declining triacylglycerols in the
second half. Overall, a functional choline deficiency was not attained
in the present studies as it was for the men in the previous study by
Zeisel et al. (1991)
. This may simply be because Zeisel
et al. fed a zero-choline diet, whereas the diets fed in the present
studies contained about one-third of the choline in a typical Western
diet.
Clearly, the biosynthesis of choline is inadequate to maintain choline
status when dietary intake of both choline and folate is even
marginally low. This may be not only because choline is utilized as a
source of methyl groups in the absence of folate, but also because de
novo synthesis of phosphatidylcholine from phosphatidylethanolamine
(Fig. 1)
may be impeded by decreased methylation capacity. Restoration
of plasma phosphatidylcholine concentrations when folate but not
choline was repleted suggests that folate-dependent methylation of
phosphatidylethanolamine was limiting rather than lack of substrate
(choline) for synthesis of phosphatidylcholine via the CDP-choline
pathway.
These results support in part the contention of Zeisel et al. (1991)
that "choline is an essential nutrient for humans when
excess methionine and folate are not available in the diet." However,
our finding that methionine intake of 1400 mg/d does not prevent
choline depletion during low-folate intake suggests again that folate
is a critical limiting factor to provide methyl groups for these
pathways. The significant decrease in plasma phosphatidylcholine
concentrations in the men receiving 238 mg/d of dietary choline
suggests that more than 250 mg/d of dietary choline is required by
adults to maintain plasma choline and phosphatidylcholine when folate
intake is low. The sensitivity of choline status to folate nutriture
may well be more serious for infants and children than for adults
because both folate and choline are critical nutrients for growth.
These results confirm, in humans, some aspects of the metabolic
interdependence of folate and choline previously demonstrated in rats.
Because low-folate status is associated with increased risk of birth
defects and elevated plasma homocysteine (Selhub and Rosenberg 1996
), a risk factor for vascular disease, further studies of
folate-choline interactions, particularly on how choline nutriture may
modulate the human folate requirement, are needed.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Presented in part at Experimental Biology '98,
April 20, 1998, San Francisco, CA [Jacob, R., Jenden, D., Okoji, R.,
Allman, M. & Swendseid, M. (1998) Choline status of men and women is
decreased by low dietary folate. FASEB J. 12: A512].
2 Reference to a company or product name does not
imply approval or recommendation of the product by the U.S. Department
of Agriculture to the exclusion of others that may be suitable.
3 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
5 Abbreviations used: ALT, alanine aminotransferase;
AST, aspartate aminotransferase; HPLC, high pressure liquid
chromatography; MCV, mean corpuscular volume; PC, phosphatidylcholine;
RDA, Recommended Dietary Allowance; SAM, S-adenosylmethionine; WHNRC,
Western Human Nutrition Research Center.
Manuscript received July 16, 1998. Initial review completed August 11, 1998. Revision accepted November 30, 1998.
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