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Betaine, an important nutritional component for humans, has been reviewed in the synopsis. Its chemical structure, synthesis, utilization and physiological significance have been discussed. Due to its ability to donate a methyl group, it plays a pivotal role in numerous pathways, including the methionine cycle. A betaine-deficient diet can disturb several cellular processes. Therefore, betaine supplementation to ameliorate certain pathological conditions has been envisaged.

Betaine, also referred to as trimethyglycine, oxyneurine and glycine-betaine is a naturally occurring human nutrient that was first discovered in sugar beets and was later found in several micro-organisms, marine invertebrates, plants and animals. Chemically, it is a neutral methyl derivative of glycine with a positively charged tri-methylammonium group and a negatively charged carboxyl group (Figure 1.1), a specific type of zwitterion that performs methylation in addition to osmoregulation (Craig, 2004).

Figure 1.1

The structure of betaine. Structure of glycine-betaine, also known as trimethyglycine and oxyneurine.

Figure 1.1

The structure of betaine. Structure of glycine-betaine, also known as trimethyglycine and oxyneurine.

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Humans can obtain their daily intake of betaine (1–2.5 g) from exogenous sources such as wheat bread (201 mg per 100 g), beets (114–297 mg per 100 g), spinach (600–645 mg per 100 g) and wheat bran (1339 mg per 100 g) or it can be synthesized endogenously from its metabolic precursor choline (Craig, 2004). Dietary betaine is absorbed from the duodenal enterocytes into circulation and maintained between 20 and 70 µmol L−1 with a median plasma concentration of 27.8 µmol L−1, although being slightly higher in men than in women (Lever et al., 1994; Awwad et al., 2014). It is carried to the liver and kidneys where it is catabolized by a series of enzyme-catalyzed reactions, predominantly in the mitochondria, and participates in the methionine cycle. Here, betaine donates a methyl group to homocysteine to form N,N-dimethylglycine and l-methionine via the enzyme betaine-homocysteine methyltransferase (BHMT). This is a zinc thiol-enzyme expressed mainly in the liver and kidneys that also functions in glycine, serine and threonine metabolisms (Pajares and Perez-Sala, 2006). The transmethylation reaction mediated by BHMT not only helps to detoxify homocysteine but also increases serum methionine levels (Storch et al., 1991) and S-adenosylmethionine (SAM) (Barak et al., 1993), which itself serves as a methyl donor in DNA methylation and many anabolic pathways of phospholipids, hormones and proteins. Removal of betaine from the body is primarily by metabolism with minimal urinary excretion, even after high amounts of betaine consumption (Lever and Slow, 2010).

Uncatabolized betaine acts as an osmolyte and confers protection to the cells against environmental stresses like osmotic irregularity, adverse temperatures and dehydration. By regulating the surface tension of water, it aids in water retention and thereby maintains cellular volume. Some examples of its osmoregulatory performances are the hydration of albumin, where it forms a single layer of water around albumin (Courtenay et al., 2000), hydration and transport of molecules across the intestine (Kettunen et al., 2001) and sustenance of haemoglobin solvation (Hundahl et al., 2003). Additionally, while betaine can protect renal cells from high concentrations of electrolytes (Horio et al., 2001) it also protects myosin in the skeletal muscle from urea-induced structural changes (Ortiz-Costa et al., 2002) Thus, betaine helps to preserve the optimal functions of several organs and cell types. Interestingly, hepatic and renal concentrations of betaine and its availability as an osmoprotectant are controlled by the regulation of BHMT, which in turn, is dependent on tonicity (Pajares and Perez-Sala, 2006).

Since betaine provides methyl groups, lack of betaine in the diet can cause hypomethylation and elevated homocysteine and reduced SAM concentrations resulting in perturbed methionine metabolism. In addition, a betaine-deficient diet can lead to liver steatosis (Craig, 2004) and increase the predisposition to stroke, cardiovascular disorders, Alzheimer's (Kittner et al., 1999; Finkelstein, 2000; Seshadri et al., 2002) and atypical DNA methylation leading to carcinogenesis (Cooney, 1993). A betaine- or choline-rich diet can increase the plasma concentrations of methionine, and thereby the rate of methylation and consequently lower the risk of various neoplasms (Nitter et al., 2014; Zeng et al., 2014) and also decrease homocysteine levels in patients with inherited disorders homocysteinemia and homocystinuria (Dudman et al., 1993; Tangerman et al., 2000). Alongside, several animal studies have been conducted that present betaine as a promising therapeutic agent. Based on these studies, betaine-mediated restoration of normal DNA methylation of specific genes to ameliorate the pathogenesis of nonalcoholic fatty liver disease and alcoholic liver disease has been envisaged (Dou et al., 2014; Wang et al., 2014). In alcohol-fed animals betaine prevented and partially reversed alcoholic liver damage by increasing SAM levels and decreasing liver injury caused by endoplasmic reticulum stress (Barak et al., 1997).

  • Betaine helps to maintain the normal physiological functions of vital organs like the heart, liver, brain and kidneys.

  • It acts as an osmolyte and as a methyl donor, whereby it plays an important role in the methionine cycle.

  • Lack of betaine in the diet can result in hypomethylation, elevated homocysteine and reduced SAM concentrations.

  • This could cause disturbances in numerous biochemical pathways and lead to diverse physiological implications.

  • Animal studies and preliminary studies with human subjects suggest that betaine supplementation can attenuate the pathogenesis of several diseases.

  • Further investigation is required to elucidate the mechanism of action of betaine, along with clinical trials to determine suitable pharmaceutical dosage and the consequences of prolonged supplementation.

  • It is caused due to excessive alcohol consumption.

  • It is manifested as liver damage and can show a wide variety of symptoms.

  • The disease encompasses several stages of liver damage beginning from increased deposition of fat, followed by inflammation and excessive collagen production, subsequently leading to severe liver scarring.

  • Alcohol abstinence during the early stages can prevent the progression of the disease.

  • DNA methylation – Addition of methyl group(s) to adenine or cytosine residues on the DNA. It is one of the ways in which gene expression is regulated.

  • Haemoglobin solvation – Refers to the solubility of haemoglobin in an aqueous environment; here in the plasma.

  • Homocystinuria and homocysteinemia – Genetic disorders of methionine metabolism that elevate homocysteine levels in blood.

  • Hypomethylation – Reduction in methylation.

  • Liver steatosis – Deposition of high amounts of fats in the liver.

  • Methylation – Addition of methyl group(s).

  • Osmoprotectant – A molecule that protects the cells/organisms from osmotic pressures.

  • Thiol-enzyme – An enzyme that contains sulfhydryl group, i.e. the –SH group

  • Transmethylation – Transfer of methyl group from one molecule to another.

  • Zwitterion – A molecule that has both positive and negative charge(s) and is therefore electrically neutral.

BHMT

Betaine-homocysteine methyltransferase

SAM

S-Adenosylmethionine

1.
Awwad
 
H. M.
Kirsch
 
S. H.
Geisel
 
J.
Obeid
 
R.
Measurement of concentrations of whole blood levels of choline, betaine, and dimethylglycine and their relations to plasma levels
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
2014
, vol. 
957
 (pg. 
41
-
45
)
2.
Barak
 
A. J.
Beckenhauer
 
H. C.
Badakhsh
 
S.
Tuma
 
D. J.
The effect of betaine in reversing alcoholic steatosis
Alcoholism: Clinical and Experimental Research
1997
, vol. 
21
 (pg. 
1100
-
1102
)
3.
Barak
 
A. J.
Beckenhauer
 
H. C.
Junnila
 
M.
Tuma
 
D. J.
Dietary betaine promotes generation of hepatic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration
Alcoholism: Clinical and Experimental Research
1993
, vol. 
17
 (pg. 
552
-
555
)
4.
Cooney
 
C. A.
Are somatic cells inherently deficient in methylation metabolism? A proposed mechanism for DNA methylation loss, senescence and aging
Growth, Development and Aging
1993
, vol. 
57
 (pg. 
261
-
273
)
5.
Courtenay
 
E. S.
Capp
 
M. W.
Anderson
 
C. F.
Record, Jr.
 
M. T.
Vapor pressure osmometry studies of osmolyte-protein interactions: implications for the action of osmoprotectants in vivo and for the interpretation of “osmotic stress” experiments in vitro
Biochemistry
2000
, vol. 
39
 (pg. 
4455
-
4471
)
6.
Craig
 
S. A.
Betaine in human nutrition
American Journal of Clinical Nutrition
2004
, vol. 
80
 (pg. 
539
-
549
)
7.
Dou
 
X.
Xia
 
Y.
Chen
 
J.
Qian
 
Y.
Li
 
S.
Zhang
 
X.
Song
 
Z.
Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine supplementation in a mouse model of alcoholic liver disease
British Journal of Pharmacology
2014
, vol. 
171
 (pg. 
4073
-
4086
)
8.
Dudman
 
N. P.
Wilcken
 
D. E.
Wang
 
J.
Lynch
 
J. F.
Macey
 
D.
Lundberg
 
P.
Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology
Arteriosclerosis and Thrombosis
1993
, vol. 
13
 (pg. 
1253
-
1260
)
9.
Finkelstein
 
J. D.
Homocysteine: a history in progress
Nutrition Reviews
2000
, vol. 
58
 (pg. 
193
-
204
)
10.
Horio
 
M.
Ito
 
A.
Matsuoka
 
Y.
Moriyama
 
T.
Orita
 
Y.
Takenaka
 
M.
Imai
 
E.
Apoptosis induced by hypertonicity in Madin Darley canine kidney cells: protective effect of betaine
Nephrology, Dialysis, Transplantation
2001
, vol. 
16
 (pg. 
483
-
490
)
11.
Hundahl
 
C.
Fago
 
A.
Malte
 
H.
Weber
 
R. E.
Allosteric effect of water in fish and human hemoglobins
Journal of Biological Chemistry
2003
, vol. 
278
 (pg. 
42769
-
42773
)
12.
Kettunen
 
H.
Peuranen
 
S.
Tiihonen
 
K.
Betaine aids in the osmoregulation of duodenal epithelium of broiler chicks, and affects the movement of water across the small intestinal epithelium in vitro
Comparative Biochemistry and Physiology, Part A: Molecular and Integrative Physiology
2001
, vol. 
129
 (pg. 
595
-
603
)
13.
Kittner
 
S. J.
Giles
 
W. H.
Macko
 
R. F.
Hebel
 
J. R.
Wozniak
 
M. A.
Wityk
 
R. J.
Stolley
 
P. D.
Stern
 
B. J.
Sloan
 
M. A.
Sherwin
 
R.
Price
 
T. R.
Mccarter
 
R. J.
Johnson
 
C. J.
Earley
 
C. J.
Buchholz
 
D. W.
Malinow
 
M. R.
Homocyst(e)ine and risk of cerebral infarction in a biracial population: the stroke prevention in young women study
Stroke
1999
, vol. 
30
 (pg. 
1554
-
1560
)
14.
Lever
 
M.
Sizeland
 
P. C.
Bason
 
L. M.
Hayman
 
C. M.
Chambers
 
S. T.
Glycine betaine and proline betaine in human blood and urine
Biochimica et Biophysica Acta
1994
, vol. 
1200
 (pg. 
259
-
264
)
15.
Lever
 
M.
Slow
 
S.
The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism
Clinical Biochemistry
2010
, vol. 
43
 (pg. 
732
-
744
)
16.
Nitter
 
M.
Norgard
 
B.
De Vogel
 
S.
Eussen
 
S. J.
Meyer
 
K.
Ulvik
 
A.
Ueland
 
P. M.
Nygard
 
O.
Vollset
 
S. E.
Bjorge
 
T.
Tjonneland
 
A.
Hansen
 
L.
Boutron-Ruault
 
M.
Racine
 
A.
Cottet
 
V.
Kaaks
 
R.
Kuhn
 
T.
Trichopoulou
 
A.
Bamia
 
C.
Naska
 
A.
Grioni
 
S.
Palli
 
D.
Panico
 
S.
Tumino
 
R.
Vineis
 
P.
Bueno-De-Mesquita
 
H. B.
Van Kranen
 
H.
Peeters
 
P. H.
Weiderpass
 
E.
Dorronsoro
 
M.
Jakszyn
 
P.
Sanchez
 
M.
Arguelles
 
M.
Huerta
 
J. M.
Barricarte
 
A.
Johansson
 
M.
Ljuslinder
 
I.
Khaw
 
K.
Wareham
 
N.
Freisling
 
H.
Duarte-Salles
 
T.
Stepien
 
M.
Gunter
 
M. J.
Riboli
 
E.
Plasma methionine, choline, betaine, and dimethylglycine, in relation to colorectal cancer risk in the European prospective investigation into cancer and nutrition (Epic)
Annals of Oncology
2014
, vol. 
25
 (pg. 
1609
-
1615
)
17.
Ortiz-Costa
 
S.
Sorenson
 
M. M.
Sola-Penna
 
M.
Counteracting effects of urea and methylamines in function and structure of skeletal muscle myosin
Archives of Biochemistry and Biophysics
2002
, vol. 
408
 (pg. 
272
-
278
)
18.
Pajares
 
M. A.
Perez-Sala
 
D.
Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?
Cellular and Molecular Life Sciences
2006
, vol. 
63
 (pg. 
2792
-
2803
)
19.
Seshadri
 
S.
Beiser
 
A.
Selhub
 
J.
Jacques
 
P. F.
Rosenberg
 
I. H.
D’agostino
 
R. B.
Wilson
 
P. W.
Wolf
 
P. A.
Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease
New England Journal of Medicine
2002
, vol. 
346
 (pg. 
476
-
483
)
20.
Storch
 
K. J.
Wagner
 
D. A.
Young
 
V. R.
Methionine kinetics in adult men: effects of dietary betaine on l-[2H3-methyl-1-13C]methionine
American Journal of Clinical Nutrition
1991
, vol. 
54
 (pg. 
386
-
394
)
21.
Tangerman
 
A.
Wilcken
 
B.
Levy
 
H. L.
Boers
 
G. H.
Mudd
 
S. H.
Methionine transamination in patients with homocystinuria due to cystathionine beta-synthase deficiency
Metabolism
2000
, vol. 
49
 (pg. 
1071
-
1077
)
22.
Wang
 
L. J.
Zhang
 
H. W.
Zhou
 
J. Y.
Liu
 
Y.
Yang
 
Y.
Chen
 
X. L.
Zhu
 
C. H.
Zheng
 
R. D.
Ling
 
W. H.
Zhu
 
H. L.
Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet
Journal of Nutritional Biochemistry
2014
, vol. 
25
 (pg. 
329
-
336
)
23.
Zeng
 
F. F.
Xu
 
C. H.
Liu
 
Y. T.
Fan
 
Y. Y.
Lin
 
X. L.
Lu
 
Y. K.
Zhang
 
C. X.
Chen
 
Y. M.
Choline and betaine intakes are associated with reduced risk of nasopharyngeal carcinoma in adults: a case-control study
British Journal of Cancer
2014
, vol. 
110
 (pg. 
808
-
816
)
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