Biohacking: Cholesterol

 What is Cholesterol?

"Cholesterol is essential for our bodies to function and without cholesterol you would die. In fact, "the majority of the cholesterol in our blood comes from our own bodies making it. I don't think a lot of people understand that concept. People mistakenly think they get most of their cholesterol from their food and that's not true. Cholesterol is used to make hormones like estrogen and testosterone, is transported into the adrenal gland to aid in hormone synthesis, repair nerves, and make bile for fat digestion, it's a structural component of our cells, it synthesizes vitamin D—it plays such a critical role in our body that we genuinely need it."

Cassie Bjork, RD, in Cholesterol Clarity, page 29 by Jimmy Moore, Eric Westman, MD.

"it is an essential structural component of all animal cell membranes"

"...also serves as a precursor for the biosynthesis of steroid hormones, bile acid, and vitamin D"

"Since cholesterol is essential for all animal life, each cell is capable of synthesizing it"

"Most ingested cholesterol is esterified, and esterified cholesterol is poorly absorbed."

"Cholesterol is recycled in the body. The liver excretes it in a non-esterified form (via bile) into the digestive tract. Typically, about 50% of the excreted cholesterol is reabsorbed by the small intestine back into the bloodstream."

Wikipedia article, Cholesterol

The Straight Dope

The series by Peter Attia is one of the most accessible and informative lectures on Cholesterol that I have found.  Here are some excerpts.

"...standard cholesterol testing (including VAP) is largely irrelevant and you should have a lipoprotein analysis using NMR spectroscopy ...This topic bears an upsettingly parallel reality to that of nutrition 'science' in that virtually all health care providers have no understanding of it and seem to only reiterate conventional wisdom (e.g., 'LDL is bad,' 'HDL is good')"

"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."

"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')"

"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)."

"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."

"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."

"Only free or unesterified cholesterol (UC) can be absorbed through gut enterocytes."

"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)."

"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."

"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."

"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!"

"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."

by Peter Attia, M.D., in The Straight Dope on Cholesterol – Part 1

Bad Cholesterol, Argument & Rebuttal

Argument: "Heart disease is caused by too much "bad" cholesterol (LDL-C)"

Rebutal: "Atherosclerosis is caused by an inflammatory response to sterols in artery walls. Sterol delivery is lipoprotein-mediated, and therefore much better predicted by the number of lipoprotein particles (LDL-P) than by the cholesterol they carry (LDL-C)"

by Peter Attia, M.D., in When does heart disease begin (and what this tells us about prevention)? does 'good' cholesterol end up in places it doesn't belong and cause 'bad' problems?

"...atherosclerosis – the accumulation of sterols and inflammatory cells within an artery wall which may (or may not) narrow the lumen of the artery."

"To be clear, statistically speaking, this condition (atherosclerotic induced ischemia or infarction) is the most common one that will result in the loss of your life. For most of us, atherosclerosis (most commonly within coronary arteries, but also carotid or cerebral arteries) is the leading cause of death, even ahead of all forms of cancer combined. Hence, it's worth really understanding this problem."

"Cholesterol and triglycerides are not soluble in plasma (i.e., they can't dissolve in water) and are therefore said to be hydrophobic."

"To be carried anywhere in our body, say from your liver to your coronary artery, they need to be carried by a special protein-wrapped transport vessel called a lipoprotein."

"As these 'ships' called lipoproteins leave the liver they undergo a process of maturation where they shed much of their triglyceride "cargo" in the form of free fatty acid, and doing so makes them smaller and richer in cholesterol."

"Special proteins, apoproteins, play an important role in moving lipoproteins around the body and facilitating their interactions with other cells. The most important of these are the apoB class, residing on VLDL, IDL, and LDL particles, and the apoA-I class, residing for the most part on the HDL particles."

"Cholesterol transport in plasma occurs in both directions, from the liver and small intestine towards the periphery and back to the liver and small intestine (the 'gut')."

"The major function of the apoB-containing particles is to traffic energy (triglycerides) to muscles and phospholipids to all cells. Their cholesterol is trafficked back to the liver. The apoA-I containing particles traffic cholesterol to steroidogenic tissues, adipocytes (a storage organ for cholesterol ester) and ultimately back to the liver, gut, or steroidogenic tissue."

"All lipoproteins are part of the human lipid transportation system and work harmoniously together to efficiently traffic lipids. As you are probably starting to appreciate, the trafficking pattern is highly complex and the lipoproteins constantly exchange their core and surface lipids."

by Peter Attia, M.D., in The Straight Dope on Cholesterol – Part 2

"The sine qua non of atherosclerosis is the presence of sterols 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.

"The progression from a completely normal artery to an atherosclerotic one which may or may not be "clogged" follows a very clear path: an apoB containing particle gets past the endothelial layer into the sub-endothelial space, the particle and its cholesterol content is retained and oxidized, immune cells arrive, an initially-beneficial inflammatory response occurs that ultimately becomes maladaptive leading to complex plaque."

"While inflammation plays a key role in this process, it's the penetration of the apoB particle, with its sterol passengers, of the endothelium and retention within the sub-endothelial space that drive the process."

"The most numerous apoB containing lipoprotein in this process is certainly the LDL particle, however Lp(a) (if present) and other apoB containing lipoproteins may play a role."

by Peter Attia, M.D., in The Straight Dope on Cholesterol – Part 4

Heart Disease is a Carbohydrate Problem

"If you look at the advanced lipid tests - LDL-P, ApoB, and the size and density of the LDL—then heart disease becomes a carbohydrate problem. As long as you're focusing on LDL cholesterol as the culprit, then you can blame saturated fat."

Gary Taubes, in Cholesterol Clarity, page 114 by Jimmy Moore, Eric Westman, MD.

"Insulin resistance is important because it is the root cause of atherosclerosis. A random blood sugar level above 120, lots of small particles or Pattern B LDL cholesterol, remnant lipoproteins, elevated CRP levels, low GlycoMark, and A1c around 5.0–5.3 are the things that make me want to work up a patient more earnestly. You don't really need to do fancy advanced lipid testing; triglycerides, HDL, and non-HDL numbers are available on every standard lipid panel."

Dr Rocky Patel, in Cholesterol Clarity, page 118 by Jimmy Moore, Eric Westman, MD.

LDL-P is the best predictor of adverse cardiac events

"The same patterns are observed: 1) LDL-P is the best predictor of adverse cardiac events. 2) LDL-C is only a good predictor of adverse cardiac events when it is concordant with LDL-P; otherwise it is a poor predictor of risk. Amazingly the persons with the worst survival had low (below median) LDL-C but high LDL-P. The patients most likely to have high LDL-P with unremarkable or low LDL-C are those with either small LDL particles, or TG-rich / cholesterol poor LDL particles, or both (e.g., insulin resistant patients, metabolic syndrome patients, T2DM patients). This explains why small LDL particles, while no more atherogenic on a per particle basis than large particles, are a marker for something sinister."

by Peter Attia, M.D., in The Straight Dope on Cholesterol – Part 6

"If you want to stop atherosclerosis, you must lower the LDL particle number."

"If you were only 'allowed' to know one metric to understand your risk of heart disease it would be the number of apoB particles (90-95% of which are LDLs) in your plasma ... If this number is high, you are at risk of atherosclerosis. Everything else is secondary."

by Peter Attia, M.D., in The Straight Dope on Cholesterol – Part 4

"There's an increasing consensus that measuring particle concentrations of LDL—the whole particle, not just its cholesterol content—is a more meaningful and, in many cases, a more accurate means for assessing risk. And even more importantly, for defining goals of treatment. This whole area of particle testing has been categorized as 'emerging' technology, even though it's been emerging for three decades now."

Dr Ronald Krauss, in Cholesterol Clarity, page 98 by Jimmy Moore, Eric Westman, MD.

Triglycerides help you understand LDL

"Triglycerides are as tied to heart disease as LDL. There are two kinds of LDL: the large, buoyant variety that is not associated with heart disease, and the small, dense variety, which is definitely associated with heart disease. The best way to determine which LDL you predominantly have is by looking at your triglycerides level. High LDL and high triglycerides mean you have a preponderance of Small LDL-P, insulin resistance, and metabolic syndrome. That is what I am looking for when I run a cholesterol panel."

Dr Robert Lustig, in Cholesterol Clarity, page 105 by Jimmy Moore, Eric Westman, MD.

"I look for several things. I like to see a good, solid HDL number that is at least 10 points higher than what most labs consider 'normal' values. Triglycerides should be under 150; I don't believe as strictly that triglycerides must be below your HDL number as long as they are below 150. And finally, I check the fasting glucose and hemoglobin A1c."

Dr Cate Shannon, in Cholesterol Clarity, page 117 by Jimmy Moore, Eric Westman, MD.

Age, the single greatest risk factor

"Any guesses as to what the greatest single risk factor is for heart disease? ... It's age. Age trumps everything. In this sense, atherosclerosis is an “integral” disease (in the calculus sense of the word) — meaning it's a disease of compounding injuries, as I painstakingly went through above. Age = persistent exposure to LDL-P/apoB."

by Peter Attia, M.D., in When does heart disease begin (and what this tells us about prevention)?

Cholesterol. Inflammation. What can we hack?

"We've long known that atherosclerosis is an inflammatory disease. In the absence of inflammation or injury to the endothelial cell, the cholesterol would never go through the arterial wall and it would never stay there."

Dr. Dwight Lundell, in Cholesterol Clarity, page 37 by Jimmy Moore, Eric Westman, MD.

"When we're talking about inflammation, I like to look at what's causing it. If the client's C-reactive protein levels are high, I want to look for the root cause of the inflammation and what's causing the damage. Things like smoking, excessive alcohol consumption, consuming trans fats and processed carbohydrates, having high blood sugar levels, chemical exposure, high blood pressure, and stress can all contribute to this. Everything on this list is very different than blaming inflammation on a high-fat diet, which is what many trusted professionals will point their finger at right away."

Cassie Bjork, RD, in Cholesterol Clarity, page 38 by Jimmy Moore, Eric Westman, MD.

Hacking LDL-P/apoB

"Of the thousands and thousands of patients I have personally seen over the years with coronary disease, I can count the number of people who lacked a prevalence of small LDL particles on one hand. It is possible for it to happen, but it's highly unusual. The vast majority of people who have coronary disease or a risk of developing it have an excess of small LDL particles. There's only one thing that causes small LDL particles and that's carbohydrates, not dietary fat. We use a low-carb diet to eliminate the expression of small LDL, which also, by the way, reduces blood sugar levels and normalizes blood vitamin D levels."

Dr. William Davis, in Cholesterol Clarity, page 99 by Jimmy Moore, Eric Westman, MD.

Hacking Triglycerides / HDL

"There isn't a drug that lowers triglyceride levels well, which is why mainstream medical doctors don't pay much attention to them. But triglycerides respond very strongly to dietary changes. If you reduce your carbohydrate intake, you tend to have ideal triglyceride levels, in the 50 to 60 range. Additionally, the triglyceride-to-HDL ratio is a good indicator of how well your diet is dialed in. If the ratio is high, you might benefit from eating more saturated fats and fewer carbs."

Paul Jaminet, in Cholesterol Clarity, page 104 by Jimmy Moore, Eric Westman, MD.

Hacking hs-CRP

"Elevated CRP can signal many different conditions, including cancer, cardiovascular disease, infection, and autoimmune conditions such as rheumatoid arthritis, lupus, and inflammatory bowel disease. The chronic inflammation behind an elevated CRP level may also be influenced by genetics, a sedentary lifestyle, too much stress, and exposure to environmental toxins such as secondhand tobacco smoke. Diet has a huge impact, particularly one that contains a lot of refined, processed and manufactured foods."

Dr. Andrew Weil, M.D., in Elevated C-reactive Protein (CRP)

"There are now 34 large-scale prospective studies that have all come to the same conclusion: CRP is one of the most consistent risk stratifiers that we have. But it is important to think beyond CRP as a simple marker for high risk of disease. It also tells us something about the underlying biology."

"...patients with metabolic syndrome and high CRP have very high risk. Clearly, when the inflammatory mechanisms are engaged, metabolic syndrome patients do much worse"

"The patients with the very highest levels of hsCRP - 5 to 10, 10 to 20, or even greater than 20 mg/L—are, in fact, at the very highest risk."

"These data help to explain why those with periodontal disease, arthritis, and other systemic inflammatory disorders all have higher vascular risk. Perhaps inflammation from any cause has an adverse effect on the vascular endothelium."

"There are over 50 papers about the impact of exercise on inflammatory markers and event reduction ... Moreover, CRPs fell whether or not the patients actually lost weight. The exercise benefit was independent of weight loss."

Paul M. Ridker, MD, MPH, FACC, in C-Reactive Protein, Inflammation, and Cardiovascular Disease