You will learn
#1 How your body traffics its main energy source (fat) to your cells
#2 How your body uses dietary fat versus stored body fat
#3 What the different fat-carrying ‘vehicles’ tell you about your metabolism
#4 What Remnant Cholesterol tells you about your heart disease risk
1. How is fat trafficked in the body for energy?
As touched on in the article about triglycerides, trafficking of fat based energy through the body, in the case of triglyceride transportation, is mostly mediated by particles called lipoproteins.
Lipoproteins, among other things, are transport vehicles for various fat soluble substances in the body including cholesterol, vitamins like A, D, E, and K, and a fat-based fuel source for our cells – triglycerides.
This transportation is necessary because while the “cargo” of lipoproteins is hydrophobic (doesn’t mix with water, like oil), the bloodstream is mostly composed of water. So the fats and water in the bloodstream must be separated to successfully get this cargo to your cells for use.
Lipoproteins: more than simple energy delivery guys
They do this through special proteins called apolipoproteins. Some of these proteins can be added or removed to the lipoprotein as its “status” changes (such as amount of triglyceride being carried).
But some of these proteins stay with the lipoprotein for the duration of its time in the system. One example of this non-removable category of protein is apolipoprotein B (apoB).
The first and primary job of lipoproteins with the unique “apoB” identifier is to get energy to your cells when you need it.
This is crucial in the case of a fasted state, or in the case of fat-based fueling such as a ketogenic diet. Why? Fatty acids must be supplied to tissues that can burn them so that glucose can be saved for tissues that really need it like your brain, red blood cells, testicular sertoli cells and so on – lest these cells starve and die!
Fat you eat vs fat you store on your body
There are 2 primary contexts in which fat-metabolism occurs and, perhaps unsurprisingly, 2 main types of apoB containing lipoproteins to handle them. The first context involves dietary fat that has just been eaten.
As fat is digested in the gut, it is packaged into lipoprotein “containers” called chylomicrons which transport the fat to cells for use. The second situation involves fat from storage sites around the body (i.e. fat tissue).
Fat cells (adipocytes) release fat into circulation, which binds to albumin and is carried through the blood. Some of this fat is absorbed by other cells for use but most will be absorbed by the liver.
From there, it is then repackaged into VLDL (Very Low Density Lipoproteins). So, the transportation of fat you absorb from your food, and the fat you release into circulation from your fat cells is balanced between apoB containing lipoproteins.
Dave Feldman has demonstrated this balancing act in a series of clever self-experiments which have impressed both researchers and layperson alike.
These 2 lipoproteins, along with IDL (intermediate density lipoproteins) make up what are called Remnant Lipoproteins – which, when high, have been correlated with an increased risk of heart disease and higher all-cause mortality . But, why would this be? First, let’s address what the different particles are and how they work.
2. What are chylomicrons?
Chylomicrons are the largest lipoprotein particle, their large size is necessary in order to accommodate the large amounts of dietary fat that they carry (in the form of triglycerides).
When you ingest fat and it is broken down in the small intestine, in order for this fat to eventually be used to feed your hungry cells, it needs to make its way through the water-filled (aqueous) environment that is your bloodstream.
To do this, these fats are repackaged into chylomicrons. This happens because chylomicrons can move through water-based environments with, especially the bloodstream. These chylomicrons already come with two apolipoproteins: apolipoprotein A (apoA) and apolipoprotein B-48 (apoB-48).
ApoB-48 is like a caller ID for chylomicrons, a unique identifier. It cannot be removed and will stay attached to the chylomicron for its entire lifespan.
However, when it is first created, a chylomicron does not have the very important identifier – apolipoprotein C-II (apoC-II). Without apolipoproteinC-II, chylomicrons would be unable to supply energy to cells, and this would impede their clearance from circulation.
Friends of chylomicrons
Another lipoprotein called HDL (High Density Lipoprotein) supplies the apoC-II and apolipoprotein E (apoE) to chylomicrons.
Chylomicrons are then able to supply energy to cells around the body, including skeletal muscles (such as the muscles of the arm or leg), cardiac muscle (of the heart), and others. Transportation of this fat energy to cells is the chylomicron’s primary job.
Once the triglycerides they carry have been dropped off, chylomicrons then become chylomicron remnants. These remnants are lower in apoC-II, and higher in apolipoprotein E. Apolipoprotein E is a tag that allows the liver to clear the remnants from circulation .
3. What is VLDL?
To transport fat that comes from storage (e.g. fat cells or leftover triglycerides from chylomicron transportation) there is another lipoprotein to handle this job called VLDL (Very Low Density Lipoproteins). VLDL has the unique identifier apolipoprotein B-100.
Like chylomicrons it also acquires apoE and apoC-II among others. Because VLDL has apoE and apoC-II it can be inferred that it also has a direct role in energy distribution, and can be cleared by the liver just like chylomicrons. Instead of being made in the intestines, however, VLDL is made in the liver, and the production rate is based on how much fat (fatty acids) are available from food and fat stores .
Typically, these “free fatty acids” in the bloodstream are released from fat cells or chylomicron “spillover” and are called non-esterified fatty acids (NEFAs). When NEFAs are absorbed by the liver, it prompts further triglyceride production, leading to further VLDL production.
When insulin drops, fat cells open their ‘exit’ doors, allowing for the release of NEFAs from storage into the bloodstream . The release of NEFAs from fat cells can also happen when those cells aren’t working as they normally do, and resist the call of insulin (a condition called insulin resistance).
This will mean more NEFAs are available to the liver from circulation, and production of VLDL will rise.
This higher VLDL from NEFA release from fat cells can be observed in leaner individuals who fast for multiple days, as Dave Feldman has demonstrated, where this effect is likely to ensure plenty of fats for hungry cells to eat.
This is also seen when someone gets lab work back showing high fasting triglycerides (hypertriglyceridemia).
Status update! Lipoproteins do it too
As triglycerides are removed from VLDL, and provided to cells, the VLDL particle becomes smaller.
When it gets smaller its classification changes to IDL (Intermediate Density Lipoproteins).
These particles can either be taken up by the liver through receptors responsible for binding to lipoproteins carrying an apoE (eg: chylomicron remnants and IDL), or they can interact with hepatic lipase.
What hepatic lipase does is remove even more triglycerides from the IDL particle, thus creating LDL (Low Density Lipoproteins) which can then be used for other roles such as in the immune system, cellular growth or repair, and hormone synthesis .
Regardless of which path VLDL takes, once its triglyceride delivery has been completed, its job is done. It is then either broken down (catabolized) by the liver or remodeled into an LDL particle.
4. How are triglycerides removed from the lipoproteins?
In order to remove triglycerides from the lipoproteins, cells use what is called a lipase.
A lipase takes a triglyceride, and removes the glycerol backbone converting the triglyceride into free fatty acids. This process is called lipolysis.
These fatty acids can then be taken up by the cell through specialized receptors.
The act of turning free fatty acids back into a triglyceride, for storage or transportation, is called esterification in case you were wondering.
A lipase for every job
There are different types of lipases, including hepatic lipase (made mostly by the liver), lipoprotein lipase (on fat cells, muscle cells, and cardiac tissue), pancreatic lipase, and endothelial lipase (present on endothelial cells).
Regardless of location, the lipase does its job to take the fat from the transport particles so that the fat can be used for energy immediately or stored for later use.
What usually happens is that, after you’ve eaten, the all-important hormone insulin is released from the pancreas.
Blood insulin levels rise and lipoprotein lipase activity in fat tissue increases so that the fat cells can take up triglycerides from lipoproteins and store them. Inversely, in a fasted state when insulin is low, lipoprotein lipase activity in fat cells decreases, and activity in muscle tissue increases .
In other words, if insulin goes up fat will be stored, and when insulin is lower fat will be used by the tissues for energy. However, this can become disordered, such as in pathological (harmful) insulin resistant states.
Basically, what insulin resistance means is that insulin is ‘shouting’ but the cells aren’t ‘hearing’ it. This both decreases the actions of lipoprotein lipase in fat cells, and at the same time impairs the ability of insulin to inhibit release of fatty acids from the fat cells.
It messes up energy homeostasis . The downstream effect is that the liver has to make more transport particles (VLDL) to transport the newly created triglycerides. This increases something called remnant cholesterol . High levels of remnant cholesterol could be a sign that the system is in serious trouble. No bueno.
The job of a lipase is to break apart triglycerides so they can be taken up by cells.
Insulin usually helps to regulate this process by acting as a manager for lipoprotein lipase – it tells it when to be more active or less active in different cells. But, if fat cells become resistant to insulin’s effects, this disrupts this system and is reflected by higher levels of remnant cholesterol.
This may mean that remnant cholesterol can be used as a helpful marker for keeping an eye on how well your fat can ‘hear’ insulin.
5. What is remnant cholesterol?
Remnant cholesterol is the sum of all cholesterol carried by lipoproteins which distribute energy as their primary job.
These are called remnant lipoproteins. They include VLDL, IDL and chylomicrons . Failure to use or store the triglycerides they carry – like in the case in insulin resistance and metabolic syndrome – can lead to higher remnant cholesterol.
High fasting remnant cholesterol has been correlated with higher risk of ischemic heart disease, and higher all-cause mortality (death from all causes) . But, it may not be the particles themselves that cause this correlation – rather, it may be a reflection of metabolic disruption and insulin resistance.
ApoB: the bad boy with a heart of gold?
Although apoB containing lipoproteins have many functions in the body, including usage in the immune system, tissue growth/repair, and the inflammatory response, their first and primary role is to supply energy to cells via interactions between apoC-II and lipoprotein lipase.
Without these lipoproteins’ ability to supply energy during times without food, even shorter periods such as an overnight fast or during times when you rely on fat for energy such as when following a low-carb/ketogenic diet, the survival of humans would be greatly impaired.
There are some genetic conditions which may cause impaired usage of these lipoproteins, including apoC-II deficiency or lipoprotein lipase deficiency, and these can result in hypertriglyceridemia and high fasting levels of lipoprotein remnants .
Other factors that may contribute to high fasting remnant cholesterol include insulin resistance/metabolic syndrome.
As such, remnant cholesterol may work as a useful “system marker”, especially when paired with other markers. Remnant cholesterol can help figure out if your metabolism is functioning normally and if those lipoproteins are succeeding in their main job of maintaining smooth energy delivery to your body’s cells.
6. What are desirable fasting levels of remnant cholesterol, and how do I calculate it?
Calculating your remnant cholesterol is easy, because remnant cholesterol is merely a measure of the cholesterol carried by chylomicrons, VLDL, and IDL.
So, all you need is Total cholesterol, LDL cholesterol, and HDL cholesterol that you can get from a standard lipid panel to figure out what your remnant cholesterol levels are.
The formula looks like the following: Total cholesterol – LDL-C – HDL-C = Remnant Cholesterol If you would like to calculate your remnant cholesterol and see where you place in terms of risk based on the current research, you can also use the Cholesterol Code report tool. In a fasted state* a remnant cholesterol level under 20 mg/dL (0.52 mmol/L) appears to be desirable.
Just be aware that the science is still evolving fast on remnant cholesterol. *12-14 hours; fasting less than 12 and more than 14 hours can confound results
#1 The primary job of chylomicrons and VLDL is to transport energy (triglycerides) so we can use or store it – without them, we’d be in a lot of trouble!
#2 In order to get this energy to cells we need to use Lipoprotein Lipase to turn these triglycerides into free fatty acids so cells can take them up
#3 These processes can become deranged when fat tissue becomes insulin resistant which can be reflected through a marker called Remnant Cholesterol
#4 Remnant Cholesterol levels correlate with risk for heart disease, and all-cause mortality, perhaps because they reflect a disrupted, sick metabolism
#5 To calculate your Remnant Cholesterol, just take your Total Cholesterol, and subtract out LDL cholesterol and HDL cholesterol. The remainder is your Remnant Cholesterol.
ABOUT THE AUTHOR
This post was written by Siobhan Huggins (@siobhan_huggins)
Bio: After meeting Dave Feldman at Ketofest 2017, Siobhan’s passion for lipidology was ignited and she was driven to research all she could in a mad attempt to figure out how lipids were involved in the immune system and chronic diseases.
She has since written 2 articles that have been published on cholesterolcode.com – on plaque development and LDL modification – and has appeared as a guest in video lectures and podcasts.
Siobhan has been on a ketogenic diet since August 2016 and promptly lost over 70 pounds, reversed her hypertension and stabilized her blood sugars. She practices what she preaches because it’s backed by rigorously research.
Siobhan has dedicated herself to decoding the mysteries of cholesterol and is eager to continue learning and teaching others about the science of health and nutrition.
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