Trait: Choline Metabolism
Dr Haran Sivapalan
March 2, 2020
What is choline?
Choline is an essential micronutrient that is needed for several functions in the body, including:
- making and maintaining cell membranes
- facilitating signalling within cells
- transporting lipids
- producing neurotransmitters (nerve signalling molecules)
- carrying out various metabolic reactions
Before we go into detail about the roles of choline in the body, it’s worth unpacking the term ‘essential micronutrient.’
“Essential” refers to nutrients that we must obtain from our diet in order to survive. This is because our bodies are either incapable of making these nutrients on their own, or incapable of making them in sufficient quantities to sustain life. Choline falls into the latter category, with research suggesting that our liver’s production of choline is not enough to meet our daily needs. We therefore must get choline from the food that we eat. Foods rich in choline include eggs, liver and soybeans.
“Micronutrients” include vitamins and minerals and are nutrients that we only require in small amounts. This is in contrast to macronutrients (fat, carbohydrates and proteins), which we require in larger amounts. Strictly speaking, choline is not a vitamin, but a “vitamin-like compound.” This means that it is similar in activity to a vitamin, but is capable of being synthesized by the body.
- Choline is an essential nutrient we need for metabolic reactions and to make lipids, neurotransmitters and cell signalling molecules.
- We can produce a limited amount of choline ourselves, but this is inadequate to meet our needs.
- We need to consume choline in our diet.
What are the roles of choline in the body?
Making and maintaining cell membranes
Surrounding most cells in the body is a layer of lipids (fats and fat-like substances) that separates the interior of the cell from the outside. This layer, called a cell membrane, is important for maintaining cells’ structure, regulating what passes into and out of the cell, and coordinating communication between cells.
One major component of cell membranes is a type of lipid called a phospholipid. Phospholipids in the cell membrane are generally arranged into two opposite-facing rows, termed a “bilayer” (as shown in the diagram below), which gives the cell membrane its structural integrity.
Choline is needed to make two phospholipids in particular, both of which are key components of cell membranes:
- phosphatidylcholine (also known as lecithin)
Sphingomyelin is also part of the fatty myelin sheath that insulates our nerve fibers. This insulative layer helps to conduct to nerve signals efficiently. In this respect, choline (which is used to make sphingomyelin) is important for the function of our nervous system.
- Choline is important for making molecules called phospholipids.
- Choline is used to make phosphatidylcholine - a key component of cell membranes.
- Choline is important for healthy nerve function.
As we’ve seen in several previous traits, cells use complex cascades of chemical reactions (called signalling cascades) to carry out a variety specialized functions in response to hormones and neurotransmitters.
For example, in the Adrenaline: Baseline Level trait, we saw that the hormones adrenaline (epinephrine) and noradrenaline (norepinephrine) cause blood vessels to narrow by first binding to alpha-1 adrenergic receptors on the surface of cells. This then triggers a cascade of chemical reactions inside the cells. These cascades produce so-called second messenger molecules (e.g. IP3 and DAG) that relay the message onwards, ultimately resulting in the contraction of vascular smooth muscle and the narrowing of blood vessels.
Choline is required by cells to make two key second messenger molecules in particular:
- DAG (diacylglycerol)
These second messenger molecules are used in cell signalling pathways that regulate a variety of cell responses, including smooth muscle contraction, secretion by glands, and programmed cell death (apoptosis) in response to damage.
- Choline is required to make key molecules involved in cell signalling pathways.
- Cell signalling pathways allow cells to respond in variety of ways to stimulation from hormones, neurotransmitters and other stimuli.
Neurotransmitters are chemicals released by nerve endings that transmit impulses from one nerve to another. Choline is needed to make a neurotransmitter called acetylcholine (Ach).
Acetylcholine is particularly important for transmitting signals across the junctions between nerves and muscle fibers (called neuromuscular junctions), where it allows muscles to contract in response to a nerve impulse. Sufficient choline intake is therefore required for good motor control and muscle function.
In the brain, acetylcholine is involved in various networks, particularly those related to memory and emotion. On this note, there is some evidence that increasing choline intake can improve cognition in adults, but more research is needed.
- Choline is needed to make acetylcholine – a neurotransmitter (nerve-signalling molecule)
- Acetylcholine is important for muscle contraction, motor control, memory and other cognitive abilities.
When we eat foods containing fat, the absorbed fats (triglycerides) are first transported from the intestine to the liver for further processing. (You can read more about this in the Fat Metabolism: beta oxidation blog).
In the liver, the fats are packaged with cholesterol into particles called VLDL (very low density lipoproteins). VLDL can then transport fats in the bloodstream to various target organs, such as the skeletal muscles (where fats are used for energy) or adipose tissue (where they built into fat stores).
Choline is needed by our liver to manufacture and secrete VLDL particles.
A deficiency of choline in the diet can lead to an inability to produce VLDL and transport fats around the body. This may cause fat to accumulate in the liver instead, causing liver damage.
- Choline is needed to make VLDL particles.
- VLDL particles transport fats from the liver to other tissues via the bloodstream.
Carrying out metabolic reactions
Choline is essential for carrying out a type of metabolic reaction called methylation.
Methylation reactions play an integral role in a variety of broader processes, such as: switching genes on and off (controlling gene expression), repairing cell damage, safely getting rid of toxins, producing energy for cells and making the protective coating (myelin sheath) that surrounds nerve cells.
A methyl-group is simply a molecule that contains one carbon atom bonded to three hydrogen atoms. It has the formula -CH3. Methyl groups are typically parts of larger molecules (e.g. choline). In several different chemical reactions in the human body, methyl-groups are often donated from one molecule and attached to another. This process of adding a methyl-group is called ‘methylation.’
As we’ll see in the following section, choline gets converted into a molecule called betaine, which is involved in the methylation of a potentially harmful substance called homocysteine.
- Choline is required for important metabolic reactions called methylation reactions.
- Choline helps to regulate levels of a potentially hamrful molecule called homocysteine.
Choline, betaine, folate and homocysteine levels
Choline plays a crucial role in the metabolism of a molecule called homocysteine.
Things get a bit complicated here, so it’s well worth having a read of this blog to get a prior overview of the subject.
Homocysteine is an amino acid that is produced when we metabolize methionine: an essential amino acid that we get from foods such as meat, eggs, and nuts.
High levels of homocysteine in the bloodstream are strongly linked to an increased risk of cardiovascular disease (e.g. heart attack and stroke). It’s therefore important to keep homocysteine levels in check. So, how do we do this?
The answer lies in converting homocysteine into other molecules as part of a chemical pathway called the methionine cycle.
The methionine cycle and betaine
The methionine cycle essentially converts methionine that we get from our diet into homocysteine.
Once formed, homocysteine has two fates:
- it can be recycled back into methionine - (remethylation)
- it can be converted using Vitamin B6 into cysteine - (transsulfuration). Cysteine can then be further used to build proteins or make protective antioxidant molecules (glutathione).
Choline primarily plays a role in the first fate – the recycling of homocysteine back into methionine.
Rather than this doing directly, choline first gets converted into a molecule called betaine. This conversion is carried out by an enzyme called CHDH (choline dehydrogenase), which is encoded by the CHDH gene.
Betaine is responsible for a key methylation reaction (which we encountered in the previous section). It donates a methyl group (-CH3) to homocysteine, and converts it back into methionine.
This methylation reaction is catalysed by an enzyme called BHMT (betaine homocysteine methyltransferase), which is coded for the BHMT gene.
- Choline gets converted into a molecule called betaine.
- CHDH is the enzyme that converts choline into betaine.
- Betaine is involved in recycling homocysteine back into methionine - a type of methylation reaction.
- Betaine helps to regulate homocysteine levels.
- BHMT is the enzyme that uses betaine to convert homocysteine back into methionine.
The methionine cycle, betaine and folate
As you can see in the preceding diagram, there’s another way that homocysteine can be recycled back into methionine.
Instead of using betaine, this alternative pathway uses folate (in the form of 5-methylTH4 – folate) to donate a methyl group to homocysteine. This methylation reaction also requires Vitamin B12.
But, how does this tie in with choline?
When folate levels are low, this alternative pathway becomes less effective at recycling homocysteine back into methionine. Consequently, the other methylation pathway (which uses betaine) has to take up the slack. Accordingly, the body needs to produce more betaine. Remember, however, that betaine is made from choline. As a result, in conditions of low folate availability, our body will have a higher demand for choline.
- Folate is also used to recycle homocysteine back into methionine (remethylation).
- When folate availability is low, betaine becomes more important for recycling homocysteine into methionine.
- Sufficient intake of choline, which is used to make betaine, is particularly important when folate levels are low.
How does our body make choline?
Our liver is capable of producing choline itself, although this is generally inadequate to meet our needs and we must top this up with choline from our diet.
The exact amount of choline we need from our diet partly depends on how effectively our liver endogenously produces choline.
The first stage of choline production (synthesis) converts a molecule called phosphatidylethanolamine (PE) into another molecule called phosphatidylcholine (PC).
This reaction is carried out by an enzyme called PEMT (phosphatidylethanolamine N-methyltransferase), which is coded for the PEMT gene. Changes in activity of the PEMT enzyme will influence how effectively we make choline.
Once formed, phosphatidylcholine is subsequently converted into choline during a second stage by a class of enzymes called phospholipases.
As you may recall from a previous section, phosphatidylcholine (PC) is not just an intermediate molecule, but an important molecule in its own right – it is a phospholipid and a key component of cell membranes. It is also used to make VLDL, the myelin sheath covering nerve cells (sphingomyelin) and bile.
The activity of the PEMT enzyme, which produces phosphatidylcholine (PC), therefore also affects how well we produce various lipids and phospholipids.
- Our liver makes some choline.
- The PEMT enzyme converts PE into PC (phosphatidylcholine).
- PC is then subsequently converted into choline.
- PC is important for producing cell membranes, VLDL, bile and other lipids.
- The activity of the PEMT enzyme affects how well we produce choline.
How do genes affect my choline requirement?
Broadly speaking, the amount of choline you need to consume in food depends on two factors:
- How well your body endogenously produces choline.
- How much choline your body uses up for various functions e.g. metabolic reactions (e.g. methylation) and producing phospholipids.
Various genes can influence both these factors, thereby affecting your dietary requirement for choline.
Genes affecting production of choline
Your PEMT gene codes for the PEMT enzyme, which is responsible for the first stage of choline production (the conversion of phosphatidylethanolamine into phosphatidylcholine).
Variants of the PEMT gene can alter the activity of the PEMT enzyme, which, in turn, affect how well you produce choline.
For example, one SNP (rs7946) in the PEMT gene creates an ‘A’ allele (gene variant) associated with lower activity of the PEMT enzyme. This leads to reduced choline production, and therefore a greater need to obtain choline from the diet.
Genes affecting conversion of choline into betaine
One major use of choline is for methylation reactions.
For example, as previously described, we use choline to methylate homocysteine into methionine. For choline to be used in methylation reactions, it must first be converted into betaine. This conversion is catalysed by the CHDH enzyme.
Variants of the CHDH gene can affect the activity of the CHDH enzyme. This, in turn, influences the rate at which choline is converted into betaine.
Generally speaking, if we produce more betaine, we will use up greater amounts of choline and therefore require more choline from our diet. CHDH gene variants linked to greater CHDH activity (and thus a higher rate of betaine production) will therefore increase your dietary choline requirement.
In addition to the production of betaine, the rate at which we use betaine for methylation reactions also influences how much choline we need. Put simply, if we use up more betaine for methylation, we will also need to produce more betaine, which, in turn, will use up more choline.
As we explored earlier, methylation of homocysteine by betaine is catalysed by the BHMT enzyme. Variants of the BHMT gene linked to greater BHMT activity will therefore lead to greater betaine usage and a greater need for choline in the diet.
Genes affecting production of phospholipids
Choline is derived from the molecule phosphatidylcholine, which is used to make the phosopholipid bi-layer of cell membranes, VLDL and other lipids.
If the rate of lipid and phospholipid synthesis is high, this will lead to less phosphatidylcholine being available for conversion into choline. Consequently, more choline needs to be obtained from the diet. In this respect, gene variants that enhance the rate of phospholipid synthesis increase your dietary choline requirement.
- Genes that affect your liver's endogenous synthesis of choline influence your dietary choline requirement.
- Genes that affect your usage of choline influence your dietary choline requirement.
- Variants of your PEMT, CHDH, BHMT genes can all affect your recommended choline intake.
What are the effects of low choline intake?
A diet that is low in choline can cause damage to various organs, namely the liver and muscles. This damage can be reversed by reintroducing choline into the diet.
Note that developing full-blown choline deficiency is quite rare, but many people are at risk of having suboptimal choline levels (sometimes called choline inadequacy).
Choline is used to make VLDL, a molecule that transports fat away to other organs (e.g. the muscles or adipose tissue). When choline intake is low, VLDL production becomes compromised and so fat starts to accumulate in the liver (a process called steatosis). The accumulation of fat damages the liver and can progress to a condition called non-alcoholic fatty liver disease (NAFLD). In rare cases, this can progress to cirrhosis of the liver.
Increased risk of cardiovascular disease
Choline, via its conversion into betaine, is used to regulate homocysteine levels. When choline intake is low, homocysteine levels can rise. Elevated homocysteine levels are linked to an increased risk of heart disease and stroke.
As folate is also used to methylate homocysteine, the risk of raised homocysteine levels is particularly high when low choline intake is coupled with poor folate intake.
Insufficient choline intake during pregnancy is associated with an increased risk of an infant being born with a neural tube defect.
- Low choline intake can cause liver and muscle damage.
- Low choline intake may lead to high homocysteine levels and a greater risk of cardiovascular disease.
- Inadequate choline intake during pregnancy is linked to neural tube defects.
Am I at risk of low choline levels?
Some groups of people are at greater risk of low choline levels compared to others. These include:
People with genetic risk factors
As explained earlier, certain gene variants can either reduce choline synthesis (e.g. PEMT) or increase choline usage (e.g. CHDH). Individuals with these gene variants are more likely to have low choline levels if their diet is inadequate. Check out your personalized Insights for more information on how your genes affect your choline requirement.
Vegetarians and vegans
Eggs, milk, beef and liver are all rich sources of choline. People who follow diets which exclude these foods (e.g. vegans) may not be consuming adequate amounts of choline.
Vegan sources of choline include soybeans, mushrooms and Brussels sprouts.
Pregnancy and lactation
Pregnancy increases the body’s demands for choline as choline passes from the mother to the fetus. This puts the pregnant mother at increased risk of low choline levels. Similarly, human breast milk is rich in choline, which depletes maternal choline levels.
How much choline do I need?
According to the NIH (National Institutes of Health), the recommended daily average intake for a healthy person (known as Adequate Intake) is as follows:
Men - 550 mg per day
Women - 425 mg per day
Pregnancy - 450 mg per day
Breastfeeding - 550 mg per day
Be sure to check out your personalized actions for more information on how to optimize your choline levels.