Sunday, September 30, 2012

Lipids, Lipoproteins or Function: HDL

HDL Cholesterol and Particle Number

HDL-C is a risk factor for CVD, but in a previous post I showed examples (niacin and CETP inhibitors) where increasing HDL-C didn’t reduce CVD.  To really drive home the point here’s a study (the same one as the last post) that measured the HDL-C levels of people hospitalised for CVD.  They found that almost half had an HDL-C above 40 mg/dl


As I said before, this is an observational study, so we can’t establish cause and effect and it’s subject to confounding variables.  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 ‘HDL-C levels of 0 are associated with a reduced risk of CVD’.  What I want to show though, is that having a high HDL-C certainly doesn’t make you immune to CVD

Since LDL-P is more strongly associated with CVD than LDL-C, researchers have investigated the relationship between HDL-P and CVD and found that HDL-P is a better risk factor than HDL-C [2]

HDL Function

But the reasons why HDL is considered protective is not some linear relationship with the amount of cholesterol or the particle number, but rather the functions of HDL.  HDL function is more strongly negatively associated with CVD and HDL function doesn’t depend on HDL-C or ApoA-1 and is not associated with either, which explains the large variation in HDL-C levels in those hospitalised for CVD [3].

HDL has several functions that are considered to be protective including reverse cholesterol transport, anti-oxidative and anti-inflammatory effects, and anti-apoptotic, vasodilatory, antithrombotic, and anti-infectious activities.  HDL loses these functions and becomes ‘dysfunctional’ under conditions of oxidative stress, inflammation and infection.  High triglycerides also impairs HDL function.  Serum amyloid A (SAA) and myeloperoxidase (MPO) (two inflammatory molecules) are strongly associated with CVD and inhibit HDL function.  People with dyslipidemia or the metabolic syndrome have impaired HDL function and small dense HDL particles.  Notably, in people with the metabolic syndrome their HDLs are less effective at inhibiting LDL oxidation.  By the way, dysfunctional HDL particles are usually small and dense [4]

While a pro-inflammatory environment impairs HDL function, an anti-inflammatory environment promotes HDL function.  Regulatory T cells/IL-10 increase cholesterol efflux to HDL and reduce cholesterol uptake by macrophages, thereby safely dealing with oxLDL and oxidised cholesterol but also reducing atherosclerotic plaque [5] [6].  Evidence supporting the role of regulatory T cells/IL-10 in CVD:

  • People with CAD have about half as many Treg cells and their Treg cells have impaired functioning [7] [8]
  • Overexpressing Treg cells [9] and IL-10 [10] [11] reduces atherosclerosis in an animal models of CVD
  • IL-10 knockout mice are more susceptible to atherosclerosis [10]
  • IL-10 is associated with better CV outcomes [12]

However, one confounding variable is that oxLDL promotes apoptosis of Treg cells [13] and IL-10 production [14].  A polymorphism that decreases IL-10 by 30% isn’t associated with atherosclerosis [10] and a study finds Treg cells are not associated with atherosclerosis [15]

* The mechanism by which vitamin D is protective against CVD may be by improving Treg cell function

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