Sunday, September 23, 2012

Lipids, Lipoproteins or Function: LDL

LDL Cholesterol

LDL-C is a risk factor for CVD, but in the previous two posts I showed examples where lowering LDL-C didn’t reduce CVD.  To really drive home the point here’s a study that measured the LDL-C levels of people hospitalised for CVD.  They found that almost half had an LDL below 100 mg/dl and 17.6% had an LDL below 70 mg/dl


This is an observational study, so we can’t establish cause and effect and it’s subject to confounding variables, such as statin use for secondary prevention or people with high risk.  Also, to use this data to draw a solid conclusion it would need to be compared to population levels, otherwise one could look at this data and conclude that ‘LDL-C levels of 220 are associated with a reduced risk of CVD’.  What I want to show though, is that having a low LDL-C certainly doesn’t make you immune to CVD, far from it in fact

* Their conclusion is very different to mine “These findings may provide further support for recent guideline revisions with even lower LDL goals” [1]

The LDL Particle

But of course, why would we expect LDL-C to be definitive.  In atherosclerosis I mentioned the response-to-retention hypothesis and the oxidative modification hypothesis.  Both hypotheses relate to the LDL particle: whether it’s the LDL particle penetrating the endothelium and then getting stuck (response-to-retention); or the LDL particle’s proteins becoming oxidised (oxidative modification).

The rest of this post will briefly cover the response-to-retention hypothesis, which is discussed more in detail in the first three links at the end of the post.  But it’s equally important to remember that LDL oxidation is necessary for atherosclerosis.  I’ll mention two causes of LDL oxidation in later posts

LDL Particle Size

One explanation for variation among LDL-C in CVD is the size of the LDL particle.  There are two types/sizes of LDL: pattern A or large and buoyant (lbLDL); and pattern B or small and dense (sdLDL).  sdLDL is associated with increased triglycerides and decreased insulin sensitivity and HDL-C.  sdLDL are more vulnerable to oxidation and increase the risk of CAD by 200% [2]

The proposed mechanism is that the sdLDLs are small enough to get stuck between the endothelial cells, where they are exposed to more oxidants directly from smooth muscle cells and endothelial cells and are exposed to fewer antioxidants from the bloodstream and spend more time in the bloodstream, which increases LDL antioxidant depletion

Particle size is often used as an argument for low carb diets as diets lower in fat and higher in carbohydrates increase the number of people who predominately have sdLDL particles.


LDL Particle Number

However, sdLDL is associated with ApoB, which is a markers of LDL particle number (LDL-P).  More importantly the risk of sdLDL in CVD is dependent on ApoB, which means its value as a risk factor is abolished after adjusting for ApoB* [2] [3].

The proposed mechanism for sdLDL also has some problems.  Modified LDL is denser as the phospholipids leave the LDL particle and go to an HDL particle, and sdLDLs have a different oxidation state to regular LDLs.  So it seems like LDL oxidation precedes sdLDL [4].

LDL-P is a very a strong risk factor for CVD (stronger than LDL-C) and remains one after adjusting for sdLDL.  High LDL-P is associated with the metabolic syndrome, low HDL-C and high triglycerides.

The suggested mechanism for LDL-P is similar to sdLDL, which suggests the more LDL-P, the more likely LDL particles are to penetrate into endothelial cells, which then initiates an inflammatory response and produces atherosclerosis.  Two other factors in this model include the permeability of endothelial cells and a maladaptive immune/inflammatory response [5]

* Please don’t use this study to promote low carb diets while simultaneously ignoring LDL-P

LDL, the Thyroid and CVD

The LDL receptor is found mostly in the liver and allows LDL-C and LDL-P to be cleared from the bloodstream.  In familial hypercholesterolemia (FH) the LDL receptor is defective or absent, so LDL particles remain in the bloodstream for longer (~2.5 vs 4.5 days) and therefore LDL-C and LDL-P are elevated.  The opposite occurs with some mutations of the PCSK9 gene, where the LDL receptor is more active, LDL-C and LDL-P remain in the bloodstream for a shorter period of time and are lower.  People with FH have more CVD and people with the PCSK9 mutation have less CVD [6]

Having downregulated LDL receptors isn’t ideal: the response to retention hypothesis suggests that a higher LDL-P in the bloodstream for longer increases the number of LDL particles that will penetrate the endothelium.  The oxidative modification hypothesis suggest that the longer LDL particles remain in the bloodstream the more their antioxidants will become depleted and which can lead to the LDL particle becoming oxidised

Besides gene mutations and statins, thyroid hormone also influences the activity/concentration of the LDL receptor.  Hypothyroidism is often, but not always, associated with higher total-C, LDL-C [7] [8] and atherosclerosis/CVD [9] [10] [11].  Giving thyroid hormone to normalise low metabolic rate reduced heart attacks by 76% in old men and 85% in young men [12].  For a in depth look at the thyroid and CVD see the last link

Further Reading:
(1) The straight dope on cholesterol – Part IV
(2) The straight dope on cholesterol – Part V
(3) The straight dope on cholesterol – Part VI
(4) Thyroid Hormones and Heart Disease

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