Lipid Luminations: Elevated and Dysfunctional HDL

High density lipoprotein (HDL) has long been known as a negative risk factor for the development of atherosclerosis and cardiovascular disease. The traditional explanation of HDL’s atheroprotective effect is termed reverse cholesterol transport. In this process, HDL removes cholesterol from the periphery and delivers it to the liver to be excreted into the bile. However there are many other proposed protective mechanisms of HDL in addition to reverse cholesterol transport. HDL has components that may exert anti-inflammatory, antioxidative, antiaggregatory, anticoagulant, and profibrinolytic properties. HDL prevents endothelial dysfunction and apoptosis, stimulates the proliferation of endothelial and smooth muscle cells, inhibits chemotaxis of monocytes, and prohibits low-density lipoprotein (LDL) oxidation.(1)

With all these positive benefits of HDL, many patients with normal to elevated HDL have significant atherosclerotic burden and cardiovascular events. Furthermore, clinical studies such as the ILLUMINATE trial, which used a selective cholesterol ester transfer protein (CETP) inhibitor to raise plasma HDL-cholesterol (HDLC) levels, was terminated prematurely due to an increase in all-cause mortality in spite of an increase in HDL-C levels.(2) These findings suggest that the quantitative number of HDL particles  may not be as important as their functional properties HDL in atherosclerotic patients may have undergone a shift and become “dysfunctional.” Dysfunctional HDL is a state in which HDL not only has impaired atheroprotective function, but becomes pro-inflammatory and pro-atherogenic.

HDL dysfunction may be genetic as in the case of patients with Tangier’s Disease. In addition, HDL function may be negatively altered in clinical conditions that are associated with inflammation and oxidative stress. This HDL modification may be from acute phase response due to infection or myocardial infarction. Proinflammatory states such as diabetes mellitus, atherosclerosis, or rheumatoid arthritis also contribute to the modification of HDL function.

Multiple mechanisms have been proposed to explain how the subunits of HDL are negatively affected by inflammation.  In high inflammatory states, myeloperoxidase binds to apolipoprotein A-1(apoA-I), which oxidizes HDL and negatively affects reverse cholesterol transport.(4) Another mechanism is HDL becomes enriched with an excess of apolipoprotein C-1 (apoC-I), which inactivates CETP and causes apoptosis of aortic smooth muscle cells leading to atherosclerotic plaque rupture. Currently, many researchers are developing assays to determine the functionality of HDL as well as targeting therapies to treat HDL dysfunction.(4)

The question remains, how should we approach our patients with significantly elevated HDL? Unfortunately at this time there are not any guidelines for treatment of significantly elevated HDL. Traditionally in practice, when we encountered patients with elevated HDL-C, many providers would explain to their patients that they have a lower risk of CVD due to the protective effects of HDL. However we now know this is not always the case. Rather than commending our patients of having significantly elevated HDL-C 
concentrations we should proceed with caution.

Disclosure statement: Dr. Sheth has received honoraria from Amarin.

References 

1. Juan Salazar, Luis Carlos Olivar, Eduardo Ramos, et al.  Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics. 2015; Article ID 296417
2. Ragbir S, Farmer JA.  Dysfunctional high-density lipoprotein and atherosclerosis. Curr Atheroscler Rep. 2010 Sep;12(5):343-8.
3. Hong Feng, Xiang-An Li, Dysfunctional high-density lipoprotein. Curr Opin Endocrinol Diabetes Obes. 2009 Apr; 16(2): 156–162.
4. D’Vesharronne Moore, Catherine McNeal, Ronald Macfarlane, Isoforms of apolipoprotein C-I associated with individuals with coronary artery disease.  Biochemical and Biophysical Research Communications. 2011; 404:1034–1038.