8 Mar 2011

Lipoprotein Metabolism & Heart Disease

Lipoproteins are the microscopic vessels used to transport cholesterol, fat, and other fat-soluble nutrients around the body in our circulation.
Studying the metabolism of lipoproteins, their various pathways, regulatory mechanisms, and pathological consequences of chronic disturbances of their metabolism, potentially provides some interesting clues to the ideal composition of the human diet.
For a more detailed explanation and a collection of video tutorials go to Lipoprotein Physiology.
Dyslipidemia is defined as an abnormal amount of lipids (e.g. cholesterol and/or fat) in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to an unhealthy diet and lifestyle. 
Blood lipid levels range from normal and healthy, through to the extremes of hyperlipidemia, which if untreated can have life-threatening consequences.  

The image on the left is a 4mL sample of hyperlipidemic blood with lipids separated into the top fraction.

For the purposes of this discussion we are most interested in the dyslipidemia which is caused by poor diet and lifestyle, rather than dyslipidemias caused by genetic factors.

As detailed in my articles on Lipoprotein Physiology and Heart Disease, the complications which result in atherogenic dyslipidimea stem from alterations in lipoprotein metabolism and lipoprotein particle morphology.
The sequential domino effect leading to atherogenic dyslipidemia  is as follows:
High levels of hepatic triglyceride formation result in the formation of high numbers of large VLDL particles.  The production of irregular VLDL particles, in quantity and size, is considered to be the most significant contributing factor to unhealthy lipoprotein metabolism (Ref). 
These VLDL particles compete with chylomicrons for interaction with the lipoprotein lipase enzymes at the endothelium of the blood vessels associated with the peripheral tissues.  However, the removal of triglycerides from lipoproteins into peripheral tissues is a saturable process, reflecting the limited activity of lipoprotein lipase, this is known as the common saturable removal mechanism. 
To make matters worse for this overabundance of new large VLDL, the lipoprotein lipase enzyme has a higher affinity for chylomicrons than the VLDL particles, which means that the VLDL particles are forced to wait.  These VLDL particles therefore become susceptible to modification in circulation. 

Through the delipidation cascade, triglyceride rich VLDL become increasingly smaller and undergo further delipidation by hepatic lipase, which has an increased affinity for smaller particles, they then become precursors for the formation of atherogenic small-dense LDL particles (Ref).
These small-dense LDL are deemed more atherogenic as they either penetrate into gaps in the endothelial lining, or because they don’t bind well with the LDL receptor, leading to an excessive time in circulation (Ref , Ref), which in turn increases their susceptibility to oxidation (Ref). 

If an individual’s diet is high in omega-6 fatty acids these particles become even more prone to oxidation, thus increasing their atherogenic potential even further (Ref).
Elevated triglyceride levels also negatively impact upon HDL metabolism.  In response to elevated triglyceride levels, the actions of cholesterol ester transfer protein (CETP) causes apolipoproteins and lipids to exchange between triglyceride-rich lipoproteins and HDL particles (Ref).  This leads to triglyceride-rich HDL being more susceptible to modification by hepatic lipase (Ref), which as I detailed in here, leads to the formation of smaller HDL particles which leave circulation sooner, thus detracting from the overall positive contribution of HDL metabolism. 
The above inverse relationship between plasma triglycerides and HDL has been observed in many studies.
Putting all of the above into a nutshell:

Excessive levels of endogenous triglyceride production (High VLDL produced by the liver), results in a cascade of negative lipoprotein interactions, forming a high number of abnormal particles which are vulnerable to oxidative damage (which is exacerbated when high dietary levels of PUFA are thrown into the mix). 

When these damaged and oxidised particles are incorporated into the arterial lining, either due to a lipoprotein abnormality or simply as part of the normal process of cholesterol provision for repair of the endothelium, they trigger a spiral of inflammation and immune reactions which result in the formation of arterial plaques.
Allow the above process to occur repeatedly over a number of decades and you may unfortunately be increasing your chances of being one of the unlucky majority who dies prematurely from a heart attack!

Defining High Triglycerides
Adult Men                    Lower level = Your age                       High= 200mg/dl (2.3mmol/L)
Adult Women              Lower level = Your age                       High = 165mg/dl (1.9mmol/L)

Addressing the dietary cause of high triglycerides
In the well-fed state, when there is an excessive 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 large numbers of 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.
Increases in fasting plasma triglyceride concentrations are commonly observed during the consumption of diets with higher energy contributions from carbohydrates. 

This study  reported that a low-fat (15%), high-carbohydrate diet resulted in a 60% elevation in triglyceride production, and a 37% reduction in VLDL triglyceride clearance, when compared with a mixed diet (35% fat) of equal calories.
There is of course an even better way of elevating triglyceride levels – calorie excess from high carbohydrates, especially fructose rich carbohydrates which preferentially saturate liver glycogen stores, combined with an equally high intake of calories from dietary fats, which together will very capably clog up the common saturable removal mechanism!  But that’s just stating the obvious!
In the opposite corner, many clinical trials have demonstrated that carbohydrate restricted diets consistently improve triglyceride levels (Ref1, Ref2).
The bottom line – for a healthy heart, chronically normalise triglyceride levels and omega-6 balance by eating a calorie balanced diet, avoiding excessive carbohydrates and polyunsaturated oils.