Lipids and Cholesterol: Who Are the Players and What Are We Really Measuring?
Previous - Part 3 - LDL Studies and the Association Between LDL-C and Heart Disease, pt. 2
Having touched on the complicated history of LDL cholesterol
as the cardiovascular risk factor of choice, the following sections will
explain observed lipid behavior and its relationship with LDL-C and other risk
markers. First is what will hopefully be a simple overview (and/or reference
page) of the lipids and other molecules we’ll be discussing frequently, as well
as some common lipid-related measurements.
The major characters
in the story of lipid metabolism include:
Cholesterol – Cholesterol is a waxy organic compound
belonging to a class of molecules known as sterols. Cholesterol is critical to
cell membrane function and structure and is a precursor to Vitamin D, various
hormones, and bile acid, among other functions. Cholesterol is hydrophobic,
meaning it doesn’t interact well with water, and must therefore be carried in
the blood by lipoproteins.
Triglycerides – Triglycerides are the main form of
fat in the human body, consisting of three (hence, tri-) fatty acids bound
together. Triglycerides are trafficked through the body for energy and stored
in adipose tissue as body fat. They are also hydrophobic and, like cholesterol,
must be carried in the blood by lipoproteins.
Lipoprotein – A lipoprotein is a particle comprised
mostly of proteins and phospholipids, which are special lipid molecules with a
phosphate head that allows them to interact freely with water. The primary role
of lipoproteins in the body is to move, through the blood, molecules that
cannot otherwise travel on their own, namely cholesterol and triglycerides.
Low-Density Lipoprotein (LDL) – LDL is the most
“famous” of the lipoproteins, because it carries most of the cholesterol in
your blood at any given time. It is important to note that LDL itself is not
cholesterol, but one of many lipoprotein carrier molecules in your body.
“LDL-P” is a measure of the number of actual LDL particles themselves.
LDL-Cholesterol (LDL-C) – LDL-C is a measure of the
total cholesterol being carried by LDL particles in your blood at any given
time. This is the measurement commonly seen on a standard lipid panel, and what
people are almost always referring to when they say “bad cholesterol” or “LDL.”
While the term “LDL” is used casually to refer to LDL-cholesterol, any
reference in future posts on the topic will strictly use “LDL” to refer to the
particles themselves and “LDL-C” to refer to the measured cholesterol being
carried by those particles.
High-Density Lipoprotein (HDL) – The other famous
lipoprotein, known for its capacity to carry out “reverse cholesterol
transport” and carry cholesterol molecules away from the cells of the body.
HDL-Cholesterol (HDL-C) – Much like LDL-C, this is a
standard lipid measurement and reflects not the actual HDL particles
themselves, but the total cholesterol contained within the HDL particles in
your blood. Commonly referred to as the “good cholesterol.”
Chylomicrons – Also known as “ultra low-density
lipoproteins,” these are the primary lipoproteins involved in the trafficking
of lipids and cholesterol after eating a meal.
Very Low-Density Lipoprotein (VLDL) – VLDL are the
produced by the liver and mark the beginning of your body’s internal
lipoprotein/cholesterol trafficking system. VLDL contain large quantities of
triglycerides, and their primary role is to carry these triglycerides from the
liver to the fat and muscle cells of the body. VLDL are the precursor particle
to LDL, becoming smaller, less dense, and relatively more cholesterol-rich as
they shed triglycerides and return to the liver. These “VLDL remnants” that
return to the liver are shed of their remaining triglycerides and may reenter
the bloodstream as LDL.
What Do We Measure?
The primary or standard measurements when screening for cardiovascular
risk factors are usually just LDL-C, HDL-C, and triglycerides. As we will be
describing in future posts, these measurements are largely insufficient and, in
the case of LDL-C, arguably entirely useless.
Other markers and measures we can concern ourselves with
include:
LDL-P – The actual number of LDL particles themselves,
rather than the cholesterol within them
Apolipoprotein B – ApoB is the signature protein found
on LDL and VLDL particles. Similar to LDL-P, this represents a specific count
of LDL + VLDL particles.
VLDL-C - Like LDL-C, this is the total amount of
cholesterol contained within all the VLDL particles in the bloodstream
Oxidized LDL (OxLDL) – A reflection of how many LDL
particles have been damaged be certain chemical reactions (for example, by
exposure to free radicals). OxLDL and other damaged LDL particles are an important
factor in atherosclerosis.
Glycated LDL – A reflection of how many LDL particles
have been damaged by exposure to sugar in the bloodstream. A more common test
of overall “sugar-damage” is HbA1C, which measures red blood cells that
have sustained sugar-related damage.
LDL Particle Size – Exactly as it sounds. For reasons
that will eventually be very clear, smaller LDL particles are associated with
greater cardiovascular disease risk.
Lipoprotein (a) – A version of LDL, so to speak, that
serves as the primary receptor of oxidized phospholipids. Conventional wisdom
suggests this value is genetically fixed but, while there is a genetic
compound, it is also clearly amendable to dietary factors and seems to reflect
oxidative stress. Also known as lp(a), these particles are considered far more
dangerous than normal LDL particles.
Every marker above is a better reflection of health and cardiovascular
disease risk than is the more common LDL-C. However, LDL-C still prevails in
most medical circles and certainly in public consciousness as the marker to
fear. We will explore at length the reasons these other markers are superior
and how they change in response to dietary and lifestyle factors, but in order
to appreciate the disconnect between what we measure and what we actually care
about, let’s consider an analogy.
Suppose you want to know as much as you can about some
vehicle you’ve never seen and know nothing about. You’d like to know how large
it is, and you’d like to know how much damage is on the exterior. For all you
know it could be a shiny new Prius, a badly beaten pick-up, or even a school
bus. And those differences obviously matter! So, you ask how large the vehicle
is and how much damage it has. The answer?
“There are three people currently in the vehicle”
Did this answer your question at all? Well…you at least
know it isn’t a motorcycle, but you certainly didn’t learn anything else. And
unfortunately, that’s also the way it is with LDL-C and relevant markers of
disease. While it would be far more instructive to know the size of the vehicle
(LDL particle size) and how damaged it is (oxLDL, glycated LDL), the only thing
you’ve learned is that currently three people are sitting in there (LDL-C).
Its not a perfect analogy! By any stretch. But hopefully
that helps illustrate the difference between what we are so fixated on
measuring (LDL-C) and the host of markers that are actually more instructive in
understanding lipid behavior and cardiovascular disease risk. Exactly how those
markers indicate risk, how LDL-C really doesn’t, and how lipids behave in the
body is what we’ll begin addressing next.
Part 5 - An Energy Delivery Model: Triglyceride Production and Utilization
