Zombieland 2 - You Are What You Eat, Mommyblogger Style

First the Zombieland movie trailer, just for fun.  Now take a peek at one of my more popular posts, Zombieland, which a brilliant psychiatrist friend of mine described as "food for thought."  The post was about phospholipids, primarily phosphatidylserine and phosphatidylcholine, delectable and important nutrients nature has supplied most richly in the consumption of brains (though eggs are perhaps a more palatable source).  (Linus Pauling Institute article about choline is here.)

(Hey, Nephropal is back!  Sorry about the jump around.  I spent a good part of the morning playing video games and my attention span is shot, though my reaction times are *awesome*!)

Little did I know that choline would become a very fashionable nutrient in the paleoblogosphere.   Chris Masterjohn, Paul Jaminet, and Stephan Guyenet all did a post or three, and everyone who is anyone doubled down on his or her egg consumption thereafter.  Much of the to-do was focused on fatty liver disease (one really must eat choline to protect one's liver from the rigors of modern life).  But, as it turns out, while the liver is on the front lines, the brain is where the battle really rages.

The data in humans is... scarce (there are some small human trials of induced choline deficinecy and fatty liver, reversed by choline repletion).  But let's throw out what we have, be it epidemiology or mice or rats, and do some speculation. 

First off, choline is part of the folate cycle, which I discussed a bit in this post here.  The folate cycle is exceptionally important for liver and brain/nerve health, and includes some key players - iron, vitamin B6, vitamin B12, folate, methionine, choline, oxidized choline (called betaine), SAM, niacin, and riboflavin.  All the players need to be on the field for the full folate cycle to run efficiently.  Most choline absorbed by humans is immediately made into phosphatidylcholine and incorporated into cell membranes.  Choline is also made into betaine in the liver, where it serves as a methyl donor for many important chemical reactions (1). One of the phosphorylated products of these many reactions is phosphocreatine, by the way.  Also important to neurons and the brain is sphingomyelin.

Problems or deficiencies in the folate cycle (including choline deficiency) are implicated in fatty liver disease, neural tube defects (like spina bifida), cardiovascular disease, and cancer.   The cycle begins with methionine (an amino acid), which using various B vitamin cofactors is made into SAM.  SAM is a methyl donor and is vital in nearly sixty important chemical reactions in the liver, from making neurotransmitters to cell membranes to DNA.   After being used as a methyl donor, SAM becomes SAH which becomes homocysteine.  Having high homocysteine is associated with dementia and cardiovascular disease - in my mind it is associated with poor nutrition in general.  Without all the players, homocysteine has a hard time being recycled for use in the folate cycle again.  In order to get the majority of the players, you need to eat a lot of whole grains, or vitamins, or organ meats/eggs.   Whole grains have their issues, so I'll stick to the latter sources, thank you very much.

All right, so choline is necessary, but why?  Fatty liver develops because you need choline to make VLDL particles.  VLDL carries triglycerides from the liver into the bloodstream.  If you don't have enough phospholipids like phosphatidylcholine to form the coat of the VLDL particle, you end up with triglycerides stuck in the liver ==> fatty liver.  Now if you don't have enough phospholipids to even get your triglycerides out of the liver, how could you possibly have enough for use in your other cell membranes (or in the neurons of the brain, which are especially rich in phospholipids)?  And how would they even get there without your cholesterol/fat carrying particles?  Fatty liver is just a harbinger of even more serious problems to follow. 

Neural tube defects are extremely common birth defects that result from faulty closing of the ends of the neural tube.  In very early development, we humans spend some time being sort of flat, like an elongated pancake.  Then we roll up in a couple of ways to become more... wormlike, before we grow limb buds and all sorts of other interesting things to become babies.  Rolling up properly requires the folate cycle to be running at full efficiency.  And, sure enough, epidemiologic studies have linked choline deficiency in human mothers to neural tube defects in their offspring (those in the bottom 25% of choline intake have 4 times the risk of babies with neural tube defects as those in the top 25%), and in mice, choline restriction is shown to cause neural defects.

Pregnancy and lactation are periods in a woman's life when she needs some serious choline to keep the machinery going.  Placental/amniotic fluid levels of choline are nearly 10 times mother's serum levels (2)  Moms seem to benefit from an enhanced choline-making machinery during pregnancy, but mom still ends up with depleted levels after childbirth (which will continue during lactation).  It's best to have time to replete this vital nutrient between kiddos.

Beyond the neural tube defect issue is the memory issue.  Neural tube defects usually begin within the first month of pregnancy, so by the time you realize you are expecting, it's pretty much too late to do anything about it.  But studies of rats have shown that choline depleted mothers in the latter half of rat pregnancy results in offspring with lousy memories.  The hippocampus is the part of the brain at the epicenter of memory (and depression).   Pregnant rats who have plenty of choline seem to be able to make all the membranes, DNA, and stem cells you need to make an awesome hippocampus.  Pregnant rats without choline have baby rats who just don't remember as well.  In addition, choline supplementation in the second half of pregnancy seems to protect offspring rats from the detrimental brain effects of alcohol given to their mothers (3).  There are no studies in humans showing this link.  However, elevated human maternal homocysteine levels are linked with preeclampsia, prematurity, and low birth weight, and most studies have shown that the higher a mother's choline levels, the lower her homocysteine tends to be.

Other studies (including the Nurses Health Study and the Framingham Offspring Study) have shown that higher choline levels are associated with lower inflammatory markers of many kinds, including IL-6, TNF-alpha, and C reactive protein.  Keep in mind that in the PROSPECT-EPIC study, even those women in the highest quartile of choline intake fell below the Institutes of Medicine number for Adequate Intake of 425 mg a day for women (to get that amount, you need to eat half a pound of chicken, two eggs, and a quart of 1% milk (not sure why anyone would be drinking that, but okay)! And those are relatively rich sources!) In the Nurses' Health Study, 95% of women fell below an average daily intake of 411 mg.  In addition, nearly 50% of seem to have a genetic polymorphism where we have a hard time making methionine into choline, meaning choline becomes even more of an essential nutrient.  This fact may be why some people have bulletproof livers, and others develop fatty liver just by looking at a bottle of wine. 

The women with adequate intake in these large studies had a higher than average intake of eggs.  I wonder if choline is the reason recent studies have shown that eggs in conjunction with a calorie restricted diet seem to improve diabetes, despite all that fat and cholesterol. (I like these studies and how they seem to annihilate the lipotoxicity hypothesis). 

I find the information about choline to be convincing, and I eat eggs for breakfast about 4X a week (as do my kids).  The perinatal period where baby rats' brain development benefits from increased choline consumption can be extrapolated to about 4 years old in humans.  So eat up your eggs and offal, especially if you are a rugrat or plan to have rugrats any time soon!

*Wheat germ and soy lecithin are the richest vegetarian sources, but they won't be on my menu.