The Straight Dope on Cholesterol: 10 Things You Need to Know - Attia

The Straight Dope on Cholesterol: 10 Things You Need to Know



This is a guest post by Peter Attia and is a summary based on a 10-part series of the same name that you can find at The Eating Academy. 
 
To put this summary post and, more importantly, this 10-part series in perspective, let’s examine one of the most pervasive pieces of dietary advice given to people worldwide:

“Eating foods that contain any cholesterol above 0 mg is unhealthy.”
- T. Colin Campbell, PhD, author of The China Study.

No summary of this length can begin to fully address a topic as comprehensive as cholesterol metabolism and the pathogenesis of atherosclerosis. In fact, those of us who challenge conventional wisdom often find ourselves needing to do exactly what Frederic Bastiat suggested:

“We must admit that our opponents in this argument have a marked advantage over us. They need only a few words to set forth a half-truth; whereas, in order to show that it is a half-truth, we have to resort to long and arid dissertations.”

So, at the risk of trying to minimize the “long and arid” part of this process, below are the 10 things you need to know to be the judge – for yourself – if the conventional advice about cholesterol is correct.

1. The sine qua non of atherosclerosis is the presence of a sterol in an artery wall. How it gets there is the only thing we should be worrying about.

Contrary to popular belief, atherosclerosis is not caused by many of things we think of, such as smoking, high blood pressure, diabetes, high LDL (the so-called “bad” cholesterol), or low HDL (the so-called “good” cholesterol). Some of these are certainly markers of risk – low HDL, for example – while others accelerate the process – smoking, for example – but none of these are the direct cause of atherosclerosis.

The sine qua non of atherosclerosis is the presence of sterols (cholesterol or phytosterol) in arterial wall macrophages. Sterols are delivered to the arterial wall by the penetration of the endothelium by an apoB-containing lipoprotein, which transport the sterols. In other words, unless an apoB-containing lipoprotein particle violates the border created by an endothelium cell and the layer it protects, the media layer, there is no way atherogenesis occurs. If this is a bit confusing, don’t worry. It’s all made clear below.

2. Cholesterol is vital for life; no cholesterol = no life.

Cholesterol is a 27-carbon molecule shown in the figure below. Each line in this figure represents a bond between two carbon atoms. That’s it. Mystery over.

All this talk about “cholesterol” and most people don’t actually know what it is. So, there you have it. Cholesterol is “just” another organic molecule in our body.

I need to make one distinction that will be very important later. Cholesterol, a steroid alcohol, can be “free” or “unesterified” (“UC” as we say, which stands for unesterified cholesterol) which is its active form, or it can exist in its “esterified” or storage form which we call a cholesterol ester (“CE”). The diagram below shows a free (i.e., UC) molecule of cholesterol. An esterified variant (i.e., CE) would have an “attachment” where the arrow is pointing to the hydroxyl group on carbon #3, aptly named the “esterification site.”

One of the biggest misconceptions is that cholesterol is “bad.” This could not be further from the truth. Cholesterol is very good! In fact, there are (fortunately rare) genetic disorders in which people cannot properly synthesize cholesterol. One such disease is Smith-Lemli-Opitz syndrome (also called “SLOS,” or 7-dehydrocholesterol reductase deficiency) which is a metabolic and congenital disorder leading to a number of problems including autism, mental retardation, lack of muscle, and many others.

Cholesterol is absolutely vital for our existence. Every cell in our body is surrounded by a membrane. These membranes are largely responsible for fluidity and permeability, which essentially control how a cell moves, how it interacts with other cells, and how it transports “important” things in and out. Cholesterol is one of the main building blocks used to make cell membranes (in particular, the ever-important “lipid bilayer” of the cell membrane).

Beyond cholesterol’s role in allowing cells to even exist, it also serves an important role in the synthesis of vitamins and steroid hormones, including sex hormones and bile acids. Make sure you take a look at the picture of steroid hormones synthesis and compare it to that of cholesterol (above). If this comparison doesn’t convince you of the vital importance of cholesterol, nothing I say will.
One of the unfortunate results of the eternal need to simplify everything is that we (i.e., the medical establishment) have done the public a disservice by failing to communicate that there is no such thing as “bad” cholesterol or “good” cholesterol. All cholesterol is imperative for life to exist!

The only “bad” outcome is when cholesterol ends up inside of the wall of an artery, most famously the inside of a coronary artery or a carotid artery, AND leads to an inflammatory cascade which results in the obstruction of that artery (make sure you check out the pictures in the links above). When one measures cholesterol in the blood we really do not know the final destination of those cholesterol molecules!

3. The cholesterol we eat has little to do with the cholesterol we measure in our bloodstream.

We ingest (i.e., take in) cholesterol in many of the foods we eat and our body produces (“synthesizes”) cholesterol de novo from various precursors. About 25% of our daily “intake” of cholesterol – roughly 300 to 500 mg – comes from what we eat (called exogenous cholesterol), and the remaining 75% of our “intake” of cholesterol – roughly 800 to 1,200 mg – is made by our body (called endogenous production). To put these amounts in context, consider that total body stores of cholesterol are about 30 to 40 gm (i.e., 30,000 to 40,000 mg) and most of this resides within our cell membranes. Nearly every cell in the body can produce cholesterol, and thus very few cells actually require a delivery of cholesterol. Cholesterol is required by all cell membranes and to produce steroid hormones and bile acids.

Of this “made” or “synthesized” cholesterol, our liver synthesizes about 20% of it and the remaining 80% is synthesized by other cells in our bodies. The synthesis of cholesterol is a complex four-step process (with 37 individual steps) that I will not cover here, but I want to point out how tightly regulated this process is, with multiple feedback loops. In other words, the body works very hard (and very “smart”) to ensure cellular cholesterol levels are within a pretty narrow band (the overall process is called cholesterol homeostasis). Excess cellular cholesterol will crystalize and cause cellular apoptosis (programmed cell death). Plasma cholesterol levels (which is what clinicians measure with standard cholesterol tests) often have little to do with cellular cholesterol, especially artery cholesterol, which is what we really care about. For example, when cholesterol intake is decreased, the body will synthesize more cholesterol and/or absorb (i.e., recycle) more cholesterol from our gut. The way our body absorbs and regulates cholesterol is really amazing, so I want to spend a bit of time discussing it.

• The blue circle in this figure represents something called a Niemann-Pick C1-like 1 protein (NPC1L1). It sits at the apical surface of enterocytes and it promotes active influx (i.e., bringing in) of gut luminal unesterified cholesterol (UC) as well as unesterified phytosterols into the enterocyte. Think of this NPC1L1 as the ticket-taker at the door of the bar (where the enterocyte is the “bar”); he lets most cholesterol (“people”) in. However, NPC1L1 cannot distinguish between cholesterol (“good people”) and phytosterol (“bad people” – for reasons I won’t discuss here) or even too much cholesterol (“too many people”).

• The pink circle in this figure represents a structure called the adenosine triphosphate (ATP)-binding cassette (ABC) transporters ABCG5 and ABCG8. This structure promotes active efflux (i.e., kicking out) of unesterified sterols (cholesterol and plant sterols – of which over 40 exist) from enterocytes back into the intestinal lumen for excretion. Think of ABCG5/G8 as the bouncer at the bar; he gets rid of the really bad people (e.g., phytosterols, as they serve no purpose in humans) you don’t want in the bar who snuck past the ticket-taker (NPC1L1). Of course, in cases of hyperabsorption (i.e., where the gut absorbs too much of a good thing) they can also efflux out un-needed cholesterol. Along this analogy, once too many “good people” get in the bar, fire laws are violated and some have to go. The enterocyte has “sterol-excess sensors” (a nuclear transcription factor called LXR) that do the monitoring, and these sensors activate the genes that regulate NPC1L1 and ABCG5/G8.

There is another nuance to this, which is where the CE versus UC distinction comes in:

• Only free or unesterified cholesterol (UC) can be absorbed through gut enterocytes. In other words, cholesterol esters (CE) cannot be absorbed because of the bulky side chains they carry.
• Much (> 50%) of the cholesterol we ingest from food is esterified (CE), hence we don’t actually absorb much, if any, exogenous cholesterol (i.e., cholesterol in food).
• Furthermore, most of the unesterified cholesterol (UC) in our gut (on the order of about 85%) is actually of endogenous origin (meaning it was synthesized in bodily cells and returned to the liver), which ends up in the gut via biliary secretion and ultimately gets re-absorbed by the gut enterocyte. The liver is only able to efflux (send out via bile into the gut) UC, but not CE, from hepatocytes (liver cells) to the biliary system. Liver CE cannot be excreted into bile. So, if the liver is going to excrete CE into bile and ultimately the gut, it needs to de-esterify it using enzymes called cholesterol esterolases which can convert liver CE to UC.

4. The cholesterol in our bloodstream has little to do with the cholesterol in our artery walls (i.e., atherosclerosis).

To understand how cholesterol travels around our body requires some understanding of the distinction between hydrophobic and hydrophilic. A molecule is said to be hydrophobic (also called nonpolar) if it repels water, while a molecule is said to be hydrophilic (also called polar) if it attracts water. Think of your veins, arteries, and capillaries as the “waterways” or rivers of your body. Cholesterol is precious “cargo” that needs to move around, but it needs a “boat” to carry it.
The proteins that traffic collections of lipids are called apoproteins. Once bound to lipids they are called apolipoproteins, and the protein wrapped “vehicle” that transports the lipids are called lipoproteins. Many of you have probably heard this term before, but I’d like to ensure everyone really understands their important features. A crucial concept is that, for the most part, lipids go nowhere in the human body unless they are a passenger inside a protein wrapped vehicle called a lipoprotein. As their name suggests, lipoproteins are part lipid and part protein. They are mostly spherical structures which are held together by a phospholipid membrane (which, of course, contains free cholesterol). The figure below shows a schematic of a lipoprotein.

You will also notice variable-sized proteins on the surface of the lipid membrane that holds the structure together. The most important of these proteins are called apolipoproteins, as I alluded to above. The apolipoproteins on the surface of lipoprotein molecules serve several purposes including:

1. Assisting in the structural integrity and solubility of the lipoprotein;
2. Serving as co-factors in enzymatic reactions;
3. Acting as ligands (i.e., structures that help with binding) for situations when the lipoprotein needs to interact with a receptor on a cell.

Apolipoproteins come in different shapes and sizes which determine their “class.” Without getting into the details of protein structure and folding, let me focus on two important classes: apolipoprotein A-I and apolipoprotein B. ApoA-I is the apolipoprotein that wraps HDL particles. ApoB is the apolipoprotein that wraps VLDL, IDL, and LDL particles.

5. The only way sterols end up in artery walls – the one place we don’t want them to be – is if the sterols are carried there by an apoB-containing lipoprotein particle.

So what drives a LDL particle to do something as sinister as to leave the waterway (i.e., the bloodstream) and “illegally” try to park at a dock (i.e., behind an endothelial cell)? Well, it is a gradient driven process which is why particle number is the key driving parameter.

As it turns out, this is probably a slightly less important question than the next one: what causes the LDL particle to stay there? In the parlance of our metaphor, not only do we want to know why the boat leaves the waterway to illegally park in the dock with its precious cargo, but why does it stay parked there? This phenomenon is called “retention” in lipidology-speak.

Finally, if there was some way a LDL particle could violate the endothelium, AND be retained in the space behind the cell (away from the lumen on the side aptly called the sub-endothelial space) BUT not elicit an inflammatory (i.e., immune) response, would it matter?

I don’t know. But it seems that not long after a LDL particle gets into the sub-endothelial space and takes up “illegal” residence (i.e., binds to arterial wall proteoglycans), it is subject to oxidative forces, and as one would expect an inflammatory response is initiated. The result is full blown mayhem. Immunologic gang warfare breaks out and cells called monocytes and macrophages and mast cells show up to investigate. When they arrive and find the LDL particle, they do all they can to remove it. In some cases, when there are few LDL particles, the normal immune response is successful. But, it’s a numbers game. When LDL particle invasion becomes incessant, even if the immune cells can remove some of them, it becomes a losing proposition and the actual immune response to the initial problem becomes chronic and maladaptive and expands into the space between the endothelium and the media.

The multiple-sterol-laden macrophages or foam cells coalesce, recruit smooth muscle cells, induce microvascularization, and before you know it complex, inflamed plaque occurs. Microhemorrhages and microthrombus formations occur within the plaque. Ultimately the growing plaque invades the arterial lumen or ruptures into the lumen inducing luminal thrombosis. Direct luminal encroachment by plaque expansion or thrombus formation causes the lumen of the artery to narrow, which may or may not cause ischemia.


Read more: http://www.marksdailyapple.com/the-straight-dope-on-cholesterol-10-things-you-need-to-know-part-1/#ixzz24wyQCVFe
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The Anti-Egg Bad Scientist Strikes Again - Naughton

The Anti-Egg Bad Scientist Strikes Again

Posted by Tom Naughton

I lost count of how many people sent me emails or posted comments about the latest Eggs Will Kill You! study. Here are a couple of sample headlines and lead paragraphs:
No yolk: eating the whole egg as dangerous as smoking?

Just as you were ready to tuck into a nice three-egg omelet again, comforted by the reassuring news that eggs are not so bad for you, here comes a study warning that for those over 40, the number of egg yolks consumed per week accelerates the thickening of arteries almost as severely as does cigarette smoking. Server, can you make that an egg-white omelet instead, please?

Egg yolks almost as unhealthy as cigarettes: Study

Yolk or smoke — the first is almost as bad for you as the second, London researchers have found.
Egg yolks accelerate the thickening of arteries? As in cause and effect? Was this a carefully controlled clinical trial?

Of course not. It was yet another observational study based on a food questionnaire, as the LA Times article explains.

The study, published Tuesday in the journal Atherosclerosis, measured the carotid wall thickness — a key indicator of heart disease risk — of 1,231 patients referred to a vascular prevention clinic, and asked each to detail a wide range of their health habits, from smoking and exercise to their consumption of egg yolks. Just as smoking is often tallied as “pack-years” (the number of cigarette packs smoked per day for how many years), egg-yolk consumption was tallied as “egg yolk years” (the number of egg yolks consumed per week times the number of years they were eaten).
So what we’re looking at here is a group people who were referred to a heart-disease clinic – hardly a random sampling of the population – and a measure of their plaque levels compared to their answers on a questionnaire about their dietary habits. Here’s what you can reasonably conclude about cause and effect from a study like this:

[nothing]

But of course, that’s not how our intrepid media reporters interpreted it:
Smoking tobacco and eating egg yolks increased carotid wall thickness in similar fashion — which is to say, the rate of increase accelerated with each stair-step up in cigarette smoking or yolk consumption.

Eating yolks triggered plaque build-up at two thirds the rate for people who are smokers.
It would be bad enough if we were just witnessing the usual media misinterpretation of an observational study. But in this case, the lead (ahem) researcher has been aiding and abetting that misinterpretation. Here are some quotes from his university’s own press release:
Newly published research led by Western’s Dr. David Spence shows that eating egg yolks accelerates atherosclerosis in a manner similar to smoking cigarettes.

No, you dimwits, Dr. Spence found a correlation. That’s all.

“The mantra ‘eggs can be part of a healthy diet for healthy people’ has confused the issue. It has been known for a long time that a high cholesterol intake increases the risk of cardiovascular events, and egg yolks have a very high cholesterol content. In diabetics, an egg a day increases coronary risk by two to five-fold,” said Spence, a professor of Neurology at Western’s Schulich School of Medicine & Dentistry and the director of its Stroke Prevention and Atherosclerosis Research Centre at the Robarts Research Institute.

Dr. Spence, even Ancel Keys admitted that the amount of cholesterol we consume in our diets has no effect on the cholesterol levels in our blood. How exactly does consuming cholesterol cause heart disease? What’s the biological mechanism?

As for his statement an egg per day increases coronary risk in diabetics, I dealt with that lousy study in a previous post.

“What we have shown is that with aging, plaque builds up gradually in the arteries of Canadians, and egg yolks make it build up faster – about two-thirds as much as smoking. In the long haul, egg yolks are not okay for most Canadians.”

No, Dr. Spence, you haven’t shown that eggs make it build up faster. You can’t possibly show any such cause and effect by conducting an observational study.

Spence added the effect of egg yolk consumption over time on increasing the amount of plaque in the arteries was independent of sex, cholesterol, blood pressure, smoking, body mass index and diabetes.
Excuse me, but did I just read that the artery-clogging effects of eggs were independent of cholesterol?!! The whole reason Dr. Spence has been warning us against consuming eggs is that they contain too much cholesterol. So is cholesterol the bad guy here or not?

Let me see if I can follow the logic so far: eating eggs doesn’t raise cholesterol levels in our bloodstreams, cholesterol was not a determining factor for plaque buildup in this study, but Dr. Spence doesn’t want us to eat eggs yolks because (as he’s been busy explaining to the media), eggs contain more than the recommended amounts of cholesterol.

Okay, got it.

Here’s another of my favorite bad-science interpretations of the study:
The cholesterol in delicious egg yolks accelerates atherosclerosis (the build-up of plaque in our arteries) almost as much as smoking.

Once again, that sure sounds like cause and effect to me.

That sentence came from The Atlantic … which is a bit ironic, since the same magazine had the good sense last year to publish an excellent article titled Lies, Damned Lies and Medical Science. Perhaps whoever wrote the sentence above should read that article, which describes how Dr. John Ionnidis — an M.D. and mathematical genius who has spent years studying studies – has been exposing bad science in the health and medical fields. Here are some quotes:
He’s what’s known as a meta-researcher, and he’s become one of the world’s foremost experts on the credibility of medical research. He and his team have shown, again and again, and in many different ways, that much of what biomedical researchers conclude in published studies—conclusions that doctors keep in mind when they prescribe blood-pressure medication, or when they advise us to consume more fiber or less meat — is misleading, exaggerated, and often flat-out wrong. He charges that as much as 90 percent of the published medical information that doctors rely on is flawed.
When it came to cancer, heart disease, and other common ailments, there was plenty of published research, but much of it was remarkably unscientific, based largely on observations.

Good scientists don’t jump to conclusions based on observational studies, and with good reason: as I mentioned in my Science For Smart People speech, Dr. Ionnidis determined that 80 percent of the conclusions drawn from observational studies have turned out to be wrong. Yup, 80 percent. Here’s more from the article:
Consider, he says, the endless stream of results from nutritional studies in which researchers follow thousands of people for some number of years, tracking what they eat and what supplements they take, and how their health changes over the course of the study …

For starters, he explains, the odds are that in any large database of many nutritional and health factors, there will be a few apparent connections that are in fact merely flukes, not real health effects—it’s a bit like combing through long, random strings of letters and claiming there’s an important message in any words that happen to turn up.

Apparently in combing through his long, random strings of letters, Dr. Spence found the message Eggs Yolks Will Clog Your Arteries! – followed by another one that read: Forget What Real Scientists Believe – Correlation Does Too Prove Causation!

I don’t have a copy of the full study (and I’m not paying $32 to buy one), but Zoe Harcombe has one and wrote a spot-on analysis. One interesting bit of data she pulled from the study is that the people who ate the most eggs (or had the most “yolk years” under their belts) also had the lowest total cholesterol levels. Hmmm … once again I have to ask myself how these killer eggs yolks are clogging Canadian arteries if not through cholesterol.

She also noticed that even in the highest quintile of “egg yolks years,” the people surveyed were consuming an average of 4.68 eggs per week. According to a USDA table I downloaded, Americans in the 1920s consumed between 6 and 7 eggs per week on average. I guess that explains the sky-high rate of heart disease in the 1920s.

So what’s going on with this study? Why did Dr. Spence find a correlation? As Dr. Ionnidis points out in the Atlantic article, researchers have a way of finding the results they want to find. But let’s suppose this was a totally unbiased analysis and the correlation between “egg yolk years” and plaque buildup is really and truly right there in the data. Does that prove egg yolks cause plaque?
Nope.

As I’ve said before, if I could get the media to go along and convince everyone that celery will clog your arteries, in a decade or two we could conduct an observational study and find that – lo and behold – people who ate more celery had more heart disease. The reason we’d find that correlation is that health-conscious people would be avoiding celery, while the “I don’t give a @#$%” people wouldn’t.

We saw that effect (in reverse, anyway) with the estrogen pill fiasco. A large observational study showed that women who took estrogen pills had a 40% lower rate of heart disease. But in two large clinical trials (the kind that matter), women who took estrogen pills ended up with higher rates of both heart disease and strokes. The estrogen pills weren’t protecting women’s hearts, but health-conscious women were more likely to take estrogen pills. Health-conscious people routinely gravitate towards what they’re told is good for them and avoid what they’re told is bad for them. In doing so, they can create all kind of correlations that have nothing to do with cause and effect.
I know that, even Dr. Spence doesn’t.

We’ve been told for 35 years now that eggs yolks are bad for us. So who is going to eat fewer eggs? Health-conscious people. The “I don’t give a @#$%” types will eat more – probably with a couple of pieces of white-bread toast.

My advice to the Canadians (and anyone else who wants to avoid heart disease) is to enjoy your eggs but dump all the sugar, wheat and other refined carbohydrates from your diet.

I had four egg yolks today, courtesy of our chickens. I had three yesterday and four on Tuesday. I’ll eat more eggs tomorrow. In “egg yolk years,” I’m probably coming up on my 237th birthday. And I’m not the least bit worried about it.
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Supposed Perils Of Eating Eggs - Briffa

 Supposed Perils Of Eating Eggs

Aug, Wed 15th,  By : Dr John Briffa

 

Someone recently sent me a link to this report of a study which warns us of the supposed perils of eating eggs. The study on which the report is based [1] looked at the association between the amount of egg yolks people ate and the amount of ‘atherosclerotic plaque’ in the main arteries supplying blood to the head (the carotid arteries). The authors tells us that an association was found, even when other potential ‘confounding’ factors were taken into account such as smoking and body mass index. By their own admission, though, the authors suggest they should have perhaps included some other confounding factors too, including exercise and waist circumference. Nevertheless, the end result is the authors warning us off eating eggs. Is there concern and advice justified?

OK, let’s get something straight from the start: this study is what is referred to as an epidemiological study, which looks at associations between things, but can’t be used to determine causality (in this case, that eating eggs accelerates atherosclerosis). One relevant factor here is that eggs have suffered from an unhealthy reputation for years now, and it may be that those who eat eggs are less health-conscious on-the-whole, and perhaps are more likely to engage in genuinely life-threatening behaviours such as filling up on processed food or being very sedentary. I actually wrote about these issues most recently here, in a post entitled ‘Note to medical journalists: correlation does not prove causation’. It seems some researchers need to be reminded of this too, hence the title of this blog post.

Another fundamental problem with research of this nature as it relies on individuals reporting how much and/or often they eat of specific foods. As a patient remarked to me yesterday, most people find it difficult to recall what they ate even a couple of days ago. Self-reporting of diet is generally recognized to be hopelessly prone to error.

So, let’s summarise here the essentials of this study:

1. it found an association between egg eating and the amount of atherosclerosis in the carotid arteries
2. it controlled for some relevant confounding factors but not others
3. it relied on self-reported dietary data which is very prone to error
4. even if the study was really well done and the dietary reporting accurate, it’s still epidemiological in nature which tells us, in the end, little or nothing

Now, bear this in mind when you read this quote from the one of the study authors – Dr J David Spence – as it appears in the report I link to above:

What we have shown is that with aging, plaque builds up gradually in the arteries of Canadians, and egg yolks make it build up faster…

This stance clearly gives the impression that eating eggs yolks cause atherosclerosis, but this claim simply cannot be made on the basis of this study.
Here’s another quote from Dr Spence:

In diabetics, an egg a day increases coronary risk by two to five-fold

He’s referring to other epidemiological research here, and again his assertion is indefensible.
But maybe we shouldn’t be too surprised, here, because Dr Spence has form in this area. In a previous blog post here I detail how he, along with a co-author, makes strong claims about eggs eating based on weak evidence. What would cause a ‘scientist’ to overstate the relevance of his or her research? Many things, but here’s two:

1. Ego
Look, researchers generally like to publish ‘impactful’ stuff. Too bad that Dr Spence engages in ‘research’ that simply can’t be very impactful on the basis of it epidemiological nature. Even unconsciously there can be a tendency to ‘over-egg’ (sorry, couldn’t resist) one’s findings.

2. Conflicts of interest
As I detail in the blog post I link to above, Dr Spence has been rewarded financially in a way that gives him a vested interest in keeping the ‘cholesterol is bad’ theory alive.

References:
1. Spence JD, et al. Egg yolk consumption and carotid plaque. Circulation epub 31 July 2012
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The straight dope on Cholesterol– Part 1 (Attia)

The straight dope on Cholesterol– Part 1

Posted by Peter Attia on Apr 25, 2012

Concept #1 – What is cholesterol?

Cholesterol is a 27-carbon molecule shown in the figure below. Each line in this figure represents a bond between two carbon atoms. Sorry, I’ve got to get it out there. That’s it. Mystery over.

All this talk about “cholesterol” and most people don’t actually know what it is. So there you have it. Cholesterol is “just” another organic molecule in our body.

I need to make one important distinction that will be very important later. Cholesterol, a steroid alcohol, can be “free” or “unesterified” (“UC” as we say, which stands for unesterified cholesterol) which is its active form, or it can exist in its “esterified” or storage form which we call a cholesterol ester (“CE”). The diagram above shows a free (i.e., UC) molecule of cholesterol. An esterified variant (i.e., CE) would have an “attachment” where the arrow is pointing to the hydroxyl group on carbon #3, aptly named the “esterification site.”

Since cholesterol can only be produced by organisms in the Animal Kingdom it is termed a zoosterol. In a subsequent post I will write about a cousin of cholesterol called phytosterol, but at this time I think the introduction would only confuse matters. So, if you have a question about phytosterols, please hang on.

Concept #2 – What is the relationship between the cholesterol we eat and the cholesterol in our body?

We ingest (i.e., take in) cholesterol in many of the foods we eat and our body produces (“synthesizes”) cholesterol de novo from various precursors. About 25% of our daily “intake” of cholesterol – roughly 300 to 500 mg — comes from what we eat (called exogenous cholesterol), and the remaining 75% of our “intake” of cholesterol — roughly 800 to 1,200 mg – is made by our body (called endogenous production). To put these amounts in context, consider that total body stores of cholesterol are about 30 to 40 gm (i.e., 30,000 to 40,000 mg) and most of this resides within our cell membranes. Every cell in the body can produce cholesterol and thus very few cells actually require a delivery of cholesterol. Cholesterol is required by all cell membranes and to produce steroid hormones and bile acids.

Of this “made” or “synthesized” cholesterol, our liver synthesizes about 20% of it and the remaining 80% is synthesized by other cells in our bodies. The synthesis of cholesterol is a complex four-step process (with 37 individual steps) that I will not cover here (though I will revisit), but I want to point out how tightly regulated this process is, with multiple feedback loops. In other words, the body works very hard (and very “smart”) to ensure cellular cholesterol levels are within a pretty narrow band (the overall process is called cholesterol homeostasis). Excess cellular cholesterol will crystalize and cause cellular apoptosis (programmed cell death). Plasma cholesterol levels (which is what clinicians measure with standard cholesterol tests) often have little to do with cellular cholesterol, especially artery cholesterol, which is what we really care about. For example, when cholesterol intake is decreased, the body will synthesize more cholesterol and/or absorb (i.e., recycle) more cholesterol from our gut. The way our body absorbs cholesterol is so amazing, so I want to spend a bit of time discussing it.

In medical school, whenever we had to study physiology or pathology I always had a tendency to want to anthropomorphize everything. It’s just how my brain works, I guess, and understanding cholesterol absorption is a great example of this sort of thinking. The figure below shows a cross-section of a cell in our small intestine (i.e., our “gut”) called an enterocyte that governs how stuff in our gut actually gets absorbed. The left side with the fuzzy border is the side facing the “lumen” (the inside of the “tube” that makes up our gut). You’ll notice two circles on that side of the cell, a blue one and a pink one.

[What follows is a bit more technical than I would have liked, but I think it’s very important to understand how this process of cholesterol absorption works. It’s certainly worth reading this a few times to make sure it sinks in.]

• The blue circle represents something called a Niemann-Pick C1-like 1 protein (NPC1L1). It sits at the apical surface of enterocytes and it promotes active influx (i.e., bringing in) of gut luminal unesterified cholesterol (UC) as well as unesterified phytosterols into the enterocyte. Think of this NPC1L1 as the ticket-taker at the door of the bar (where the enterocyte is the “bar”); he lets most cholesterol (“people”) in. However, NPC1L1 cannot distinguish between cholesterol (“good people”) and phytosterol (“bad people” – I will discuss these guys later, so no need to worry about it now) or even too much cholesterol (“too many people”). [I can’t take any credit for this anthropomorphization – this is how Tom Dayspring explained it to me!]

• The pink circle represents an adenosine triphosphate (ATP)-binding cassette (ABC) transporters ABCG5 and ABCG8. This complex promotes active efflux (i.e., kicking out) of unesterified sterols (cholesterol and plant sterols – of which over 40 exist) from enterocytes back into the intestinal lumen for excretion. Think of ABCG5,G8 as the bouncer at the bar; he gets rid of the really bad people (e.g., phytosterols as they serve no purpose in humans) you don’t want in the bar who snuck past the ticket-taker (NPC1L1). Of course in cases of hyperabsorption (i.e., in cases where the gut absorbs too much of a good thing) they can also efflux out un-needed cholesterol. Along this analogy, once too many “good people” get in the bar, fire laws are violated and some have to go. The enterocyte has “sterol-excess sensors” (a nuclear transcription factor called LXR) that do the monitoring and these sensors activate the genes that regulate NPC1L1 and ABCG5,G8).

There is another nuance to this, which is where the CE versus UC distinction comes in:

• Only free or unesterified cholesterol (UC) can be absorbed through gut enterocytes. In other words, cholesterol esters (CE) cannot be absorbed because of the bulky side chains they carry.

• Much (> 50%) of the cholesterol we ingest from food is esterified (CE), hence we don’t actually absorb much, if any, exogenous cholesterol (i.e., cholesterol in food). CE can be de-esterified by pancreatic lipases and esterolases – enzymes that break off the side branches and render CE back to UC — so some ingested CE can be converted to UC.

• Furthermore, most of the unesterified cholesterol (UC) in our gut (on the order of about 85%) is actually of endogenous origin (meaning it was synthesized in bodily cells and returned to the liver), which ends up in the gut via biliary secretion and ultimately gets re-absorbed by the gut enterocyte. The liver is only able to efflux (send out via bile into the gut) UC, but not CE, from hepatocytes (liver cells) to the biliary system. Liver CE cannot be excreted into bile. So, if the liver is going to excrete CE into bile and ultimately the gut, it needs to de-esterify it using enzymes called cholesterol esterolases which can convert liver CE to UC.

• Also realize that the number one way for the liver to rid itself of cholesterol is to convert the cholesterol into a bile acid, efflux that to the bile (via a transporter called ABCB11) and excrete the bile acids in the stool (typically most bile acids are reabsorbed at the ileum).

Concept #3 – Is cholesterol bad?

One of the biggest misconceptions out there (maybe second only to the idea that eating fat makes you fat) is that cholesterol is “bad.” This could not be further from the truth. Cholesterol is very good!

 In fact, there are (fortunately rare) genetic disorders in which people cannot properly synthesize cholesterol. Once such disease is Smith-Lemli-Opitz syndrome (also called “SLOS,” or 7-dehydrocholesterol reductase deficiency) which is a metabolic and congenital disorder leading to a number of problems including autism, mental retardation, lack of muscle, and many others.

Cholesterol is absolutely vital for our existence. Let me repeat: Cholesterol is absolutely vital for our existence. Every cell in our body is surrounded by a membrane. These membranes are largely responsible for fluidity and permeability, which essentially control how a cell moves, how it interacts with other cells, and how it transports “important” things in and out. Cholesterol is one of the main building blocks used to make cell membranes (in particular, the ever-important “lipid bilayer” of the cell membrane).

Beyond cholesterol’s role in allowing cells to even exist, it also serves an important role in the synthesis of vitamins and steroid hormones, including sex hormones and bile acids. Make sure you take a look at the picture of steroid hormones synthesis and compare it to that of cholesterol (above). If this comparison doesn’t convince you of the vital importance of cholesterol, nothing I say will.
One of the unfortunate results of the eternal need to simplify everything is that we (i.e., the medical establishment) have done the public a disservice by failing to communicate that there is no such thing as “bad” cholesterol or “good” cholesterol. All cholesterol is good!

The only “bad” outcome is when cholesterol ends up inside of the wall of an artery, most famously the inside of a coronary artery or a carotid artery, AND leads to an inflammatory cascade which results in the obstruction of that artery (make sure you check out the pictures in the links, above). When one measures cholesterol in the blood – we really do not know the final destination of those cholesterol molecules!

And that’s where we’ll pick it up next time – how does “good” cholesterol end up in places it doesn’t belong and cause “bad” problems? If anyone is looking for a little extra understanding on this topic, please, please, please check out my absolute favorite reference for all of my cholesterol needs, LecturePad. It’s designed primarily for physicians, but I suspect many of you out there will find it helpful, if not now, certainly once we’re done with this series.

To summarize this somewhat complex issue

1. Cholesterol is “just” another fancy organic molecule in our body, but with an interesting distinction: we eat it, we make it, we store it, and we excrete it – all in different amounts.
2. The pool of cholesterol in our body is essential for life. No cholesterol = no life.
3. Cholesterol exists in 2 forms – UC and CE – and the form determines if we can absorb it or not, or store it or not (among other things).
4. Most of the cholesterol we eat is not absorbed and is excreted by our gut (i.e., leaves our body in stool). The reason is it not only has to be de-esterified, but it competes for absorption with the vastly larger amounts of UC supplied by the biliary route.
5. Re-absorption of the cholesterol we synthesize in our body is the dominant source of the cholesterol in our body. That is, most of the cholesterol in our body was made by our body.
6. The process of regulating cholesterol is very complex and multifaceted with multiple layers of control. I’ve only touched on the absorption side, but the synthesis side is also complex and highly regulated. You will discover that synthesis and absorption are very interrelated.
7. Eating cholesterol has very little impact on the cholesterol levels in your body. This is a fact, not my opinion. Anyone who tells you different is, at best, ignorant of this topic. At worst, they are a deliberate charlatan. Years ago the Canadian Guidelines removed the limitation of dietary cholesterol. The rest of the world, especially the United States, needs to catch up.

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