HDL & Heart Disease

High Density Lipoprotein & Heart Disease 

It is very well documented that high concentrations of the so-called "good cholesterol" - high density lipoprotein (HDL) - has protective value against cardiovascular diseases such as ischemic stroke and myocardial infarction. Low concentrations of HDL correlate with an increased risk for atherosclerotic diseases.

Similar to some of the other bio markers of cardiac risk, without wanting to willingly state the obvious, it is important to recognise that low-HDL levels are merely one of the symptoms of the cause of heart disease.

Guidelines suggest that men are at risk with HDL levels of 40 mg/dL (1.0 mmol/L) or less, whereas levels of 60 mg/dL (1.6 mmol/L) or above are described as desirable.  Women are considered to be at risk if HDL levels are 50 mg/dL (1.3 mmol/L) or less, while levels of 60 mg/dL (1.6 mmol/L) or above are described as desirable.

HDL is the smallest of the lipoprotein particles, it is also the densest lipoprotein as it contains the highest proportion of protein.

HDL carries many different types of lipid and proteins, several of which have very low concentrations but are biologically very active.  For example, HDL and their protein and lipid constituents have very important anti-inflammatory, antioxidant and anti-thrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk.

Men tend to have noticeably lower HDL levels, with smaller size and lower cholesterol content than women. This is coincidental with an increased incidence of atherosclerotic heart disease in men.

The importance of normal to high levels of HDL is reflected in the observation that people with very low LDL levels remain exposed to increased cardiac risk if their HDL levels are not high enough.

Anecdotally, I have encountered reports of individuals increasing HDL values from normal levels to over 80mg/dl, whilst decreasing triglycerides from over 150 down to 50mg/dl when adopting a very-low-carb, high saturated-fat diet.

HDL as an indirect forward transporter

The metabolism of HDL is very complex, and there are many different types of HDL. 

In a nutshell, HDL is an apoA lipoprotein which is made either by the small intestine or the liver, and in contrast to the apoB lipoproteins (Chylomicrons, VLDL, IDL, LDL) which primarily forward transport cholesterol and lipids to peripheral tissues, HDL is considered mainly as a reverse transporter of cholesterol from peripheral tissue to the liver, or to steroid producing organs such as the adrenals, ovary, and testes.

It is important not to view HDL purely as a reverse transporter.  It also plays an important role in enabling the other lipoproteins to deliver their cargos quickly and effectively.  It achieves this by sharing out key protein identification molecules to other lipoproteins in circulation; in effect HDL also functions as a lending library of identification proteins.

For example, HDL donates proteins (apoE and apoC₂) to chylomicrons which are only equipped with apoB₄₈ when they are made in the intestines. These donated proteins are essential for the chylomicrons to deliver their lipid and cholesterol cargo to peripheral tissues. 

Once the chylomicron has delivered 80% of its triglyceride contents it discards its apoC₂ protein and becomes a chylomicron remnant.  This chylomicron remnant now needs to be recycled by the liver. The chylomicron still has its apoE molecule which it got from HDL earlier, which it needs to bind with the LDL receptors at the liver, where it is absorbed and recycled. 

When VLDL is released from the liver it is equipped with the apoB₁₀₀ protein, it then picks up apoE and apoC₂ in circulation from HDL, enabling VLDL to dock at peripheral tissues and release its cargo (apoC₂ is used to dock at peripheral tissues, apoE is used to dock at the liver when it returns as a VLDL remnant). When delivering to peripheral tissues, after 50% of its triglyceride contents are deposited, VLDL discards its apoC₂ protein, becoming a VLDL remnant. 

About 50% of the VLDL remnant particles then return to the liver to be absorbed and recycled, the remainder are transformed into new LDL particles.  This occurs via the interaction of the VLDL remnant and an enzyme called hepatic lipase, which virtually empties the VLDL remnant of its triglyceride contents into the liver.  In the process the apoE identification protein is lost and returned to HDL in the circulation, creating a new LDL particle consisting of an apoB₁₀₀ protein and next to zero triglycerides.

If you have high levels of apoB lipoproteins and low levels of apoA lipoproteins, in other words high triglycerides and low HDL (Triglyceride levels and HDL levels tend to be inversely proportional), the rate of HDL’s protein lending capacity is going to be inferior to the high demand from the large number of apoB lipoproteins needing those apoE and apoC₂ proteins in order to make their deliveries.  This all contributes to increased duration of lipoprotein exposure to unfavorable modification in circulation. 

High HDL is therefore necessary for optimal forward delivery of triglycerides, which may partly explain the increased expression of HDL in response to high-fat nutrition.  This increased HDL expression may be a parallel to increased chylomicron production in the intestines in response to increased dietary fat absorption.

Hopefully, from the above description, it can be appreciated how important high HDL levels are not only as reverse cholesterol transport from tissues, but also as an essential indirect element in the forward process of triglyceride and cholesterol delivery to peripheral tissues via their protein lending capacity.

HDL’s other positive roles.

HDL’s key identification protein is apoA.  The apoA identification protein is important as it allows HDL to dock at peripheral tissue cells which need to off-load cholesterol. 

From an anti-atherogenic perspective, apoA is also very important because it enables HDL to dock at scavenger receptor sites on macrophages which have been consuming oxidised and damaged lipoproteins, facilitating the removal of their waste for return to the liver for healthy excretion, rather than being left to contribute to plaque formation. 

HDL also has an important anti-oxidant role and is responsible for delivering vitamin E to cells.   As demonstrated here, it is 3-5 times more effective than LDL at delivering vitamin E to endothelial cells. LDL appears to deliver vitamin E to these cells simply by being taken up as a whole particle, whereas HDL interacts with what could be called the "HDL receptor" and delivers vitamin E to the endothelial cell at a much faster rate than it would if it were completely consumed by the cell.

When HDL breaks down

Similar to the other lipoproteins, HDL particles can become modified by over exposure to an undesirable environment.  When serum triglyceride levels are continually elevated due to excessive carbohydrate consumption, HDL particles become enriched with triglycerides, making them better targets for hepatic lipase.  As hepatic lipase acts upon the over-fat HDL they become more and more unstable, eventually resulting in the release of their apoA identification protein, rendering them unable to carry out their vital roles.

Dietary influences upon HDL

Diets high in saturated fats and cholesterol have been shown to increase HDL levels both by increasing the transport rates and decreasing catabolic rates of HDL.  It is suggested in this study that this is perhaps as an adaptation to the metabolic load of a high fat diet.

Low-fat diets have repeatedly been found to have the opposite effect by actually decreasing healthy levels of HDL.

As with LDL particles, we also need to look at lipoprotein sub-types when looking at HDL.  Studies have found that the largest and most buoyant HDL particles (HDL2) correlate significantly with HDL's most protective effects. That is, the more HDL2 particles you have, the less your chances of having a heart attack.  Increased levels of the denser HDL3, is reportedly unrelated to reduced coronary disease.

A diet low in fat, compared to one high in total fat and saturated fat, has been demonstrated to significantly reduce levels of these large HDL lipoproteins.  This is not a short-term effect, with studies showing persistent results after 12 months.

This study found that “A reduction in dietary total and saturated fat decreased both large (HDL2 and HDL2b) and small, dense HDL sub-populations, although decreases in HDL2 and HDL2b were most pronounced.” - Berglund et al (1999).  It has also been shown that saturated and omega-3 fats selectively increase desirable large HDL.

Allow naturally healthy HDL levels to florish

In the vast majority of cases, good health is largely about you and what environment you force your body to exist in.  High and healthy HDL levels are a prime example of this.

I was going to discuss how you can elevate HDL levels, but it would be more accurate to say that the following suggestions will allow HDL levels to elevate to their natural levels.

With a healthy diet and lifestyle it is not unrealistic for your HDL levels to exceed 60+ mg/dl.

1)   Firstly and most importantly, gravitate as close as possible towards the very-low-carb, high-fat nutritional model:

• In a study of the effects of “6-month adherence to a very low carbohydrate (<25g/day) diet program”, triglyceride levels decreased 56 ± 45 mg/dL , and HDL cholesterol levels increased 10 ± 8 mg/dL.
• This low-carbohydrate, ketogenic diet study over 6 months observed many beneficial changes in serum lipid subclasses, including a 5% increase HDL particle size, and a 21% increase in large HDL.

2)   Avoid low-fat, high-carbohydrate diets:

• In controlled trials, low-fat, high-carbohydrate diets decrease HDL concentrations. The effect is strongest when carbohydrates replace saturated fatty acids, but is also seen when carbohydrates replace mono- and polyunsaturated fatty acids.  The effect is seen in both short- and long-term trials and therefore appears to be permanent. This finding is supported by epidemiological studies in which populations eating low-fat, high- carbohydrate diets were shown to have low HDL concentrations.
• It has been demonstrated that a low cholesterol, but high polyunsaturated fat diet reduced HDL by 17.4%, highlighting the importance of saturated fat in this respect; and a low cholesterol, very low-fat diet has more dramatic effects upon HDL reducing its levels by 28%.

3)   Perform regular aerobic exercise:

• Perform aerobic exercise regularly at moderate intensity (Sustained walking or light jogging is sufficient)(Ref, Ref). 
• Minimal weekly exercise volume for a modest increase in HDL levels has been estimated to be 900 kcal of energy expenditure per week or 120 minutes of low-intensity exercise per week. 
• In a study comparing runners with sedentary men, the mean HDL cholesterol level was 65 mg mg/dL in the runners and 41 mg /dL in the controls. The lipid-rich HDL2 species accounted for a much higher proportion of the HDL in runners (49% v 29%). Part of the positive adaptation here appears to be related to increased mean biologic half-life of HDL proteins, which was 6.2 days in the runners compared with 3.8 days in the sedentary men.
• In a study of “Miles Run per Week and High-Density Lipoprotein Cholesterol Levels in Healthy, Middle-aged Men” results indicate a dose-response relationship between miles run per week and increased levels of HDL. Most changes were noted in those who ran 7 to 14 miles per week at mild to moderate intensities. The HDL increase was valued at 0.3mg/dl per mile.
• In many studies changes in HDL levels are not large and it is suggested that the potential for exercise-related changes in HDL may be modest in many subjects.  However, in studies where insignificant to low exercise induced rises in total HDL are reported, results can be misleading without an accurate assessment of the HDL subfractions.  Heart healthy HDL2 can rise in line with proportional decreases in HDL3, resulting in an insignificant change in total HDL, but with an underlying very desirable upswing in HDL2 levels (Sample).

4)   Consider supplementing your diet with omega-3 fish oil:-

(Note: Due to its highly unstable nature I wouldn’t touch flax seed oil with a barge-pole! Also, the following benefits appear to be exclusive to marine derived n-3 PUFA.  If following a genuinely low-carbohydrate diet with plenty of pasture raised animal food sources supplementation is likely to be unnecessary.)

• After 8 weeks a 40% increase in HDL2 cholesterol was reported in response to supplementation of 1.88 g of eicosapentaenoic acid [EPA] and 1.48 g of docosahexaenoic acid [DHA] per day. 
• This study of 6 weeks supplementation of 2.8g/d of eicosapentaenoic acid (EPA) and 1.7g/d of docosahexaenoic acid (DHA) the levels of total HDL-cholesterol did not change, however  HDL2 increased by a whopping 74%, with a concomitant 19% decrease of HDL3.

If not following low-carb, high-sat-fat nutrition you could consider a niacin supplement (Vitamin B3):-

• Niacin has a well-documented history in the treatment of heart disease.  For an easily available and modest vitamin it has relatively powerful lipoprotein regulating ability, including a down-regulation of triglyceride, VLDL, and LDL production; whilst increasing HDL levels.
• This trial used between 1,000 and 2,000 mg/day over 12 weeks, and reported dose-proportional benefits using an extended release formula.  It is worth noting that continuous daily 24 hour exposure to niacin over an extended period can be toxic to the liver, therefore self-prescription of very-slow-release niacin should be avoided.
• However, taking niacin may be considered to be a mere biochemical shortcut.  Niacin acts through the beta-hydroxybutyrate (ketone body) receptor.  In effect by taking these large doses of niacin you are simply mimicking ketones and fooling the body into thinking that its primary fuel source is fats, creating the positive metabolic processes which ketogenic nutrition triggers – down-regulation of VLDL, decrease in TAG, increase in HDL-C, and redistribution of LDL to a larger particle size.

NOTE:   If you are eating a high-saturated fat intake with very low carbs you will have all the positive lipoprotein benefits nature intended, without touching a niacin supplement.

NOTE2:  Moderate to low alcohol consumption has inconclusive effects upon HDL levels:

• Whilst alcohol consumption correlates with both reduced coronary heart disease and increased plasma HDL cholesterol concentrations, the HDL mediated cardio-protective effects of moderate alcohol consumption appear inconclusive.  Previously reported rises in total HDL appear to be more associated with increases in the inert HDL3 with insignificant changes in the cardio-protective HDL2. [Ref1 , Ref2].
• The beneficial effects associated with the consumption of red wine with meals, appears to be more related to its capacity to reduce the susceptibility of human plasma and LDL to lipid peroxidation, rather than via possible influences upon HDL.)

Lipoprotein Physiology

Lipoproteins are macromolecular complexes, which are basically vessels used to transport cholesterol, fat, and other fat-soluble nutrients around the body in our circulation.

Firstly, I’ll identify some of the enzymes involved in lipoprotein metabolism and also some of the lipoprotein molecule components, which will help in understanding the processes.

LipoProtein Lipase (LPL) - The enzyme in many peripheral tissues which catalyses the release of their fatty acids. 

Hepatic Lipase (HL) -   This enzyme is the liver’s version of LPL.  It does not require apoC₂  to catalyse the removal of fats from lipoproteins, it also tends to have a greater affinity for smaller particles.

Cholesteryl Ester Transfer Protein (CETP) -  A plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins.

Lecithin-cholesterol acyltransferase (LCAT) -  An enzyme that converts free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of a lipoprotein particle.  The enzyme is bound to HDL and LDL particles.

Apoproteins (apo) -  are like identification badges of the lipoprotein vessels.  They tell specific receptors on the surface of cells what the lipoprotein is and what its carrying, therefore determining where the lipoproteins go, where they can dock, and where they can off-load their cargo.

apoA – the main identification apoprotein of HDL and activator of enzyme LCAT .

apoB – main identification apoprotein found in chylomicrons, VLDL, and LDL. ApoB₄₈ is specific to chylomicrons, apoB₁₀₀ is common to all other apoB particles originating from the liver (VLDL, LDL).

apoC₁ - a small apoprotein which inhibits the uptake of TG-rich lipoproteins via hepatic receptors.

apoC₂ – a small apoprotein which activates LPL. Without apoC₂ triglycerides cannot be delivered as LPL cannot be activated.  apoC₂ is reported to inhibit LCAT activity.

apoC₃ – a small apoprotein which is instrumental in the inhibition of triglyceride clearance.  When apoC₃ is dominant over apoC₂ in a particle it also inhibits the removal of that particle from circulation via apoE interference.  apoC₃ is also reported to inhibit LCAT activity.

apoE – this small apoprotein enables particles to dock with LDL receptors and deliver cholesterol.

The Chylomicron

Chylomicrons exist to deliver dietary fats (mostly triglycerides) to peripheral tissues, and to deliver dietary cholesterol to the liver.  This is known as the exogenous pathway of lipoprotein metabolism.

Chylomicrons are assembled by the small intestines as a transport mechanism for dietary fats and cholesterol.  The predominant fats in chylomicrons are triglycerides (making up 90% of their volume, only 5% is cholesterol).  The predominant apolipoproteins in chylomicrons at this stage prior to circulation are apoB₄₈ and apoA₁.

Chylomicrons leave the intestine via the lymphatic system and enter the bloodstream at the subclavian vein.  The subclavian vein is located under the collar bone on both sides of the body.  It’s a major vein which drains blood from the upper extremities and returns it to the heart. 

In the bloodstream the chylomicrons interact with other particles exchanging the smaller apolipoproteins, probably passively via gradient diffusion.  They rapidly acquire apoC₂ and apoE from plasma HDLs.   These donated proteins, apoC₂ and apoE, are essential for the chylomicrons to deliver its fatty cargo and cholesterol to peripheral tissues respectively.

In the capillaries of peripheral tissues, the fatty acids of chylomicrons are removed from the triglycerides by the action of the enzyme lipoprotein lipase (LPL).  The apoC₂ in the chylomicrons activates the LPL in the presence of phospholipid.  The fatty acids are then absorbed by the tissues and the glycerol backbone of the triglyceride is returned, in the blood to the liver and kidneys, where it is converted to a glycolytic intermediate.

As the chylomicron shrinks from the loss of its triglyceride core it needs to shed some of its shell.  Once the chylomicron has delivered 80% of its triglyceride contents it discards its apoC₂ and becomes a chylomicron remnant.  This shrinking provides unesterified cholesterol, phospholipids, and apoC₂ to HDL particles for recycling.    The chylomicron remnant is now ready to be recycled by the liver.

The chylomicron remnant uses its apoE molecule which it got from HDL earlier, to dock at the LDL receptors, or the chylomicron remnant receptors (a member of the LDL receptor family), at the liver where it is absorbed and recycled. 

Very Low Density Lipoproteins (VLDL)

This is the starting point of what is known as the endogenous pathway of lipoprotein metabolism.

VLDL is the primary lipoprotein responsible for delivery of triglycerides from the liver to peripheral tissues.  It is released from the liver equipped with the apoB100 protein; it then picks up apoE and apoC₂ in circulation from HDL.  The apoC₂ enables VLDL to dock at peripheral tissues and release its triglyceride cargo.  The VLDL particle may undergo several cycles of lipolysis as it passes through various tissues and interacts repeatedly with LPL.  As it shrinks it sheds its shell, the components of which are taken up by HDL.  Once 50% of its contents are deposited; it discards its apoC₂ protein giving it back to HDL, becoming a VLDL remnant (also known as an Intermediate Density Lipoprotein [IDL]).

 About 50% of the VLDL remnant particles then return to the liver to be absorbed (endocytosed) and recycled, the remainder stay in circulation.  While in circulation the remaining VLDL remnants return to the liver and interact with hepatic lipase, which virtually empties the VLDL remnant of its triglyceride contents into the liver.  In the process apoE is lost and returned to HDL in the circulation, creating an LDL particle consisting of an apoB100 protein and next to zero triglycerides.  The remaining apoB100 protein allows docking to peripheral tissue LDL receptor sites for delivery of essential cholesterol stores. (VLDL particles can also be converted to LDL away from the liver via interaction with HDL particles, as detailed below)

In the well-fed state, when the liver has a plentiful supply of calories, especially from carbohydrates, if the liver cannot store or oxidise incoming calories due to shear rate of delivery, or quantity in relation to available storage space, it will up-regulate hepatic glucose output (regardless of increasing plasma insulin levels) pushing the excess glucose into the blood for peripheral tissues to deal with.  Simultaneously, it will initiate de novo lipogenesis (DNL) – the creation of new fat – which is then packaged into VLDL particles for export.

This hepatic DNL has been found to only amount to about 5-10grams per day in response to carbohydrate over-feeding.  This is not a significant amount of fat when viewed purely from a body fat regulation perspective, however, from a health perspective 5-10 grams corresponds to a huge number of VLDL particles. 

Low Density Lipoproteins (LDL)

The vital supply of cholesterol to the body’s cells is achieved either by self-synthesis within the cell, or via extra-cellular supplies.

The cholesterol derived from the diet is first supplied to the liver by chylomicron remnants.  The supply of cholesterol from the liver out to the peripheral tissues is primarily the job of LDL.  They have a relatively long half-life of about 3 days, during which time they are relatively stable metabolically.

Cells in need of cholesterol recognise the passing LDL particles by their apoB₁₀₀ protein.  The LDL then docks at the LDL receptor site and is completely taken up by the cell, via LDL receptor-mediated endocytosis.  The cholesterol is then incorporated into the cell membrane where needed and any excess cholesterol is re-esterified and stored in the cell for later.

Most cells requiring cholesterol will express LDL receptors at their membrane and consume the LDL particle as a whole, only taking what they need via a self-limiting system, called the SCAP-SREBP2 system.

Macrophages are slightly different as they have special scavenger receptors which are not subject to down-regulation like normal LDL receptors.  These macrophage scavenger receptors don’t have a high affinity for normal LDL particles, but do bind enthusiastically to damaged LDL particles.

This uptake of damaged LDL particles by these scavenger receptors appears to be a normal protective mechanism; however when the numbers of damaged LDL exceeds a certain level the process becomes pathological.

High Density Lipoprotein (HDL)

The metabolism of HDL is very complex, and there are many different types of HDL. 

HDL are made by the small intestine and the liver, with the primary function of acquiring cholesterol from peripheral tissues and returning it to the liver for recycling, or excretion after conversion to bile acids.  This process is referred to as reverse cholesterol transport.

As newly created (nascent) particles, the HDLs are like deflated disc-shaped balls.  At this stage they are empty, containing no cholesterol.  The primary apoproteins of nascent HDLs are apoA, various apoC, and apoE.  As detailed earlier, a major function of HDL is to act as a lending library of apoE and apoC proteins when needed by other particles.

When taking cholesterol from peripheral tissue cells, HDL can extract it directly from the cell membranes, intracellular cholesterol stores are then mobilised to replace the cholesterol removed from the membrane, thus lowering the level of intracellular cholesterol. However, this only accounts for 20% of the reverse cholesterol transport.

The primary source of HDL reverse transport is via the interaction between HDL and immune cells.  These macrophages which have been cleaning up the aforementioned damaged LDL, interact via their scavenger receptor sites which bind with HDL’s apoA identification protein.  The nascent HDL, in effect, suck up the LDL-derived cholesterol within these macrophages and progressively change in shape from their disc appearance to larger cholesterol filled spheres, becoming HDL₂ and HDL₃ particles.

Cholesterol filled HDL particles then return mainly to the liver, or to the steroidogenic organs, and off-load their cholesterol cargo via specific docking sites called the “Scavenger Receptor BI” (SR-BI) sites.  Unlike LDL particles they are not fully consumed and internalized.

When triglyceride levels are elevated, especially when this reflects large numbers of VLDL particles, HDL transfer their cholesterol esters to VLDL, whilst triglycerides are transferred in the opposite direction from VLDL to HDL.   This is achieved using a plasma protein called CETP (Cholesterol Ester Transfer Protein).  In effect the HDLs get fatter with less cholesterol, whilst the VLDL lose fats and gain cholesterol.  This process appears to operate along a diffusion gradient and is dependent upon the number of particles in circulation – the more particles the greater the incidence of interaction.  This process converts these VLDLs into cholesterol rich and triglyceride deficient LDL particles, whilst HDL particles become triglyceride rich.

This is not an optimal scenario.  Unfortunately when HDL particles become enriched with triglycerides they become better targets for hepatic lipase.  As hepatic lipase acts upon the over-fat HDL they become more and more unstable, eventually resulting in the release of their apoA identification protein.  This makes the HDL particle unable to participate in the reverse cholesterol transport process.  This inverse relationship between plasma triglycerides and HDL has been observed in many studies. 

Lipoprotein(a)

Lipoprotein(a) binds with a percentage of LDL particles.  Whilst all LDL particles contain a single molecule of ApoB₁₀₀, only some of them have Lp(a).

The presence of the Lp(a) protein appears to indicate oxidative damage, and increases lipoprotein binding to macrophages via a high-affinity receptor that promotes foam cell formation and the deposition of cholesterol in atherosclerotic plaques.

It is therefore no surprise to learn that high levels of LDL with Lp(a) is a risk marker for atherosclerosis, cerebrovascular disease, thrombosis, and stroke.

Lp(a) concentrations vary over one thousand fold between individuals, from < 0.2 to > 200 mg/dL. This range of concentrations is observed in all populations studied so far.  

Lp(a) levels appear to be genetically predetermined and only slightly affected by diet, exercise, and other environmental factors. Commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration, although niacin (vitamin B3) and aspirin are two relatively safe, easily available and inexpensive interventions known to significantly reduce the levels of Lp(a) in some individuals.

(EDIT: There is an emerging school of thought that the presence Lp(a) may be an attempted healing reaction to oxidised tissue damage - a mechanism designed to mop up oxidised lipids from damaged tissues - the smoke rather than the fire!  It therefore makes perfect sense that dietary saturated fat would lower the fire causing the Lp(a) smoke relative to PUFA, since it's less easily oxidized. )

The Regulation of Lipoprotein Metabolism

The pathways of lipoprotein metabolism are regulated at many stages.  Not surprisingly insulin plays a major role. The main enzyme responsible for triglyceride absorption into adipose tissue is LPL, which is very sensitive to activation from insulin.

The removal of triglycerides from chylomicrons is a saturable process, reflecting the limited activity of LPL.  After a mixed carbohydrate and fat meal, chylomicrons and VLDL compete for hydrolysis by LPL.  This process is known as the common saturable removal mechanism.

LPL is known to act preferentially upon the larger chylomicron particles, therefore leaving smaller LDL particles out in the circulation until most of the larger particles have finished their business.  The rate and pattern of triglyceride clearance following a meal therefore depends upon the origin of the triglycerides.  Triglycerides which are derived from the liver, packaged into VLDL particles, are cleared slowly; whilst triglycerides derived from the duodenum and packaged into chylomicrons are processed and cleared from the circulation first.

All of the symptoms of dyslipidaemia are common among conditions in which insulin is not as effective as it should be.  When carbohydrates are not well tolerated, glucose management and disposal is inefficient, and insulin sensitivity is poor; hepatic VLDL production increases proportionately.

As can be appreciated from the above, the regulation of healthy lipoprotein metabolism depends upon an optimal balance of the various circulating lipoprotein particles.

The following provides a good CGI perspective of lipoprotein physiology:

References

Role of ApoCs in Lipoprotein Metabolism: Functional Differences Between ApoC1, ApoC2, and ApoC3

Evidence for a Common, Saturable, Triglyceride Removal Mechanism for Chylomicrons and Very Low Density Lipoproteins in Man

Metabolic Regulation: A Human Perspective.  Keith N. Frayn

Carbohydrates & Heart Disease

Is there a link between carbohydrate consumption and heart disease?

The short answer to that question is "No, not directly!"  However, in the typical modern diet, carbohydrates may be contributing to a metabolic state which is intimately involved in the development of heart disease.  This is especially relevant when eating a diet which is unnaturally high in polyunsaturated fats, and when the carbohydrates being consistently consumed are in excess of the body's capacity to use or store them, in rate or volume.

_________________________________________________

In an attempt to improve health and reduce the risk of heart disease the common mainstream nutritional advice from the health authorities is to "Reduce your animal fat and cholesterol intake and replace them with complex carbohydrates and polyunsaturated oils."   I believe that this is the worst advice a person could be given.  For a start, it makes much more sense for a person to minimize omega-6 polyunsaturated fat intake, consume lower carbohydrate levels, create a calorie deficit if ‘over-fat’, get the majority of your fat-calories from the stable saturated fats, and whatever amount of carbohydrate calories you choose to consume from fruits and vegetables rich in anti-oxidants and other phytonutrients.

When addressing heart disease risk and assessing the effects of interventions, such as diet, certain blood-borne bio-markers are used.  When reading about these, it is important to always be aware that these are just bio-markers which tend to associate with the condition.  

When using nutritional changes to address the risk of heart disease, low-carb diets do appear to have repeatedly proved successful in reducing certain blood lipid bio-markers of heart disease risk (Ref), whilst increased carbohydrate levels and reduced animal fat has been found to have the opposite effect.

For example, it has been demonstrated that reducing animal fat in the diet, and replacing it with proportionate calories from carbohydrates, will in particular increase levels of the undesirable small-dense LDL  [Ref 1 & 2 ]. This is said to be due to the increase in carbohydrates rather than the decrease in fats (Ref).  This study found that an increase in dietary saturated fat increases numbers of another desirable type of lipoprotein - large buoyant cholesterol-enriched LDL, which are found to negatively correlate with heart disease; whilst reducing small-dense sdLDL.  But as I said earlier these are just bio-markers which can divert attention away from the real background causes.

The most popular theory of the cause behind the correlation between these sdLDL and atherosclerosis appears to be a little too mechanistic.  It proposes that these pattern-B small dense LDL particles are so small that they slip through cellular gaps in the endothelial lining of the coronary arteries and cause vascular damage.


An alternative and more credible theory is that their existence is a consequence of slow and dysfunctional lipoprotein metabolism, which in turn is contributing to the cause of the atherosclerosis.


Relatively speaking, we are only able to store a limited amount of carbohydrate in our body; with individual variations affected by habitual diet, muscle mass, and physical activity levels.  This is stored mainly as glycogen in the muscles, the liver, and also in the brain in very small amounts. When these stores of glycogen become saturated and the body is faced with a continued carbohydrate intake, its first response in order to deal with the excess is to increase the use of glucose as its primary fuel in all tissues.  But these tissue will only burn what they need to meet their metabolic needs.  The remainder is either returned to the liver, or converted into fats by adipose tissue.


In the face of high carbohydrate delivery above and beyond its own capacity to store it, the liver will increase its output of glucose into the blood, even when insulin levels have increased above a point which would normally cause the liver to reduce its glucose output and start converting it into glycogen.  (Incidentally, the fructose and galactose sugar molecules preferentially stock liver glycogen and are therefore more likely to contribute to liver saturation if/when they are the dominant carbohydrate sources)

When saturated, the liver initiates de novo lipogenesis – the creation of new fat – using the excess carbohydrates to do so.  These fats are packaged into high numbers of apoB₁₀₀ particles called very low density lipoproteins (VLDL) and shipped out into the bloodstream in a rush, most likely with a poor anti-oxidant capacity.

A metaphorical lipoprotein log-jam

At this point blood glucose will be elevated, as will insulin levels, and peripheral tissues will be preferentially burning glucose and therefore have a significantly reduced uptake of fats from the lipoproteins. This is a recipe for a true lipoprotein log-jam.  Increased apoB₁₀₀ particle numbers due to ramped up VLDL production, and competition at the LPL receptor due to the common saturable removal mechanism, will increase all smaller particles’ time in circulation.


The high number of VLDL particles in circulation causes the triglyceride-rich VLDL to interact with other particles, namely LDL and HDL, over enriching them with triglycerides (via the action of cholesteryl-ester transfer protein, or CETP), which in turn reduces HDL functional capacity.

The triglyceride-rich LDL is "remodelled" during its excessive circulation by enzymes like hepatic lipase, becoming delipidated and smaller and denser, thus creating small-dense LDL. Once these particles get smaller it would appear that their clearance from circulation becomes hindered by their degenerated affinity for the LDL receptor, leading to an excessive time in circulation (Ref,Ref), which in turn further increases their susceptibility to oxidation (Ref).

If we then combine this abundance of lipoprotein molecules caused by excessive carbohydrates, and add easily oxidised polyunsaturated fats to the recipe, the outcome is obvious.  Peroxidation of the vulnerable polyunsaturated fats leads to degenerated lipoprotein particles being taken up by the endothelium as an immune response. This then leads to an inflammatory reaction, the production of foam cells, and eventually the formation of arterial plaque.

As an aside, to demonstrate that the link between high carbohydrate intakes and heart disease is not a direct one, it is worth identifying the example of the Kitavans.  This South Polynesian island population, eat generous quantities of carbohydrates. On average, they get 69% of their 2200 calories per day from high-glycemic starchy tubers and fruit (380 g carbohydrate), with not much fat to slow down digestion. Yet they have low fasting insulin, very little body fat and an undetectable incidence of diabetes, heart attack and stroke. That's despite a significant elderly population on the island and the tendency of many Kitavans to smoke like chimneys .  

However, it should be noted that they are not eating excessive calories, their diet is extremely low in omega-6 polyunsaturated fats, with only some omega-3 polyunsaturated fats from occasional fish, and their main fat source is from highly-saturated and oxidation-resistant coconut fats.

For more information of the above process see "Lipoprotein Metabolism & Heart Disease"