HDL "QUALITY"

[Fran]

Posted on SOS Yahoo group by Clare...

I recently read a review in Nature Review Nephrology which has opened
my perspective on this issue. It is more than quantity of HDL but also
QUALITY. Which makes me think of the quote by Dr. BG: "you are only as
good as your mitochondria." What I am going to try to prove is that
HDL needs to be added to that statement. In fact, dysfunctional
mitochondria through inflammation will also lead to suboptimal HDL.

HDL has the following properties:

* antioxidant
* anti-inflammatory
* anti-thrombotic
* involved in Reverse Cholesterol Transport (RCT) - meaning
bringing cholesterol from the peripheral tissues back to the liver for
processing. On the liver, HDL binds to the receptor SRB1 causing
endocytosis (engulfment).

In patients with CKD, the following occurs with HDL:

* reduction in HDL cholesterol
* impaired HDL maturation
* elevation of immature HDL
* elevated HDL triglycerides

One of the mechanisms is a decrease in the enzyme LCAT which causes
the maturation of HDL from HDL3 (small, dense) to HDL2 (large,
buoyant). (see cartoon) A heightened oxidative state (inflammation,
free radicals) causes a down regulation of LCAT and apoprotein A1 (apo
AI).

Apo AI is a primary protein of HDL involved with HDL trafficking.
Deficiency of apo-AI is associated with decreased plasma HDL levels.
Apo-AI binds with the receptor ABCA-1 on cell surfaces allowing an
efflux from the cell of phospholipids and cholesterol. Oxidative
stress inhibits the docking of apo-AI to ABCA-1. Such a interaction of
apo-AI and ABCA-1 is vital as this allows HDL to remove surplus
cholesterol from the peripheral tissues.

Furthermore, HDL by RCT is involved with picking up OXIDIZED
cholesterol and phospholipids and bringing them back to the liver.
In CKD patients, there is an elevation of HDL triglycerides due to the
decreased levels of hepatic lipase which is an enzyme causing a
clearance of triglycerides and phospholipids from HDL.

HDL possess natural antioxidant enzymes: paraoxonase and glutathione
peroxidase. Moreover, it also contains acetylhydrolase which inhibits
thrombus formation by inactivating platelet-activating factor (PAF).

In summary, inflammation not only causes an decrease in HDL and
increase in triglycerides (metabolic syndrome) but there also a
decrease in the quality of the HDL. HDL instead of being an anti-
oxidant becomes pro-inflammatory. Furthermore, the anti-platelet
capacity is decreased thus increasing the risk of thrombus formation.
Reverse Cholesterol Transport is decreased. This will allow
accumulation of oxidized cholesterol and phospholipids in the
peripheral tissues enhancing the risk of vascular disease. Why?
Macrophages will detect the oxidized cholesterol, like in LDL, and
engulf them. This will then lead to an enhanced inflammatory state
causing a recruitment of other WBCs. And as such, coronary artery
disease later appears with chronic inflammation like the metabolic
syndrome.

Acutely, inflammation, from an evolutionary standpoint, would have
been important as increased systemic cholesterol would have allowed
for an increased capacity for the formation of Vitamin D, cortisol,
aldosterone, etc. Vitamin D is known to enhance the function of the
WBCs. (click)


Vaziri ND, Navab M, Fogelman AM: HDL metabolism and activity in
chronic kidney disease. Nat Rev Nephrol. 2010 May;6(5):287-96