Unravelling the bad side of Lipoprotein(a)

Dr Torsten Kleffman (Department of Biochemistry) was recently awarded a $21,700 University of Otago Research Grant for a project on Proteomics of Lipoprotein(a): Unravelling the Bad Side of Lipoprotein(a).

A high plasma level of Lipoprotein(a) [Lp(a)] is an independent risk factor for the development of cardiovascular disease (CVD) which is a leading cause of premature death in New Zealand.

So far no known intervention has been proven to reduce Lp(a) pathogenicity in CVD.

Our proposed proteomics study (large scale mass spectrometry-based protein identification) aims at the identification of novel binding partners of Lp(a) to gain insights into the physiology and pathogenicity of Lp(a) and to identify Lp(a)-associated proteins that are responsible for atherogenic and pro-thrombotic properties of this lipoprotein particle.

Those proteins may be used as both biomarker candidates to estimate CVD risk and targets to impair Lp(a) pathogenicity.

Lipoproteins are large particles comprising a core of lipids such as trigycerides, phospholipids and cholesterol which is encapsulated by various proteins called apolipoproteins.

One of the major functions of lipoproteins is the transport of the hydrophobic lipid load through the bloodstream to and away from targeted tissues.

High density lipoprotein (HDL) mainly transports cholesterol back to the liver for clearance and is therefore attributed with anti-atherosclerotic and anti-thrombotic properties as well as being protective against CVD.

It is therefore often referred to as "good cholesterol".

Low density lipoprotein (LDL) mainly transports cholesterol from the liver to the body tissues.

It is considered "bad cholesterol" since elevated levels of LDL may be associated with atherosclerosis and myocardial infarction.

Lp(a) is gaining increasing clinical interest as a major independent risk factor of CVD.

Lp(a) is a cholesterol-rich lipoprotein particle with atherognic and pro-thrombotic properties.

Lp(a) is very similar to LDL as it contains a similar protein composition and carries a LDL-like lipid composition.

Lp(a) however, contains an additional high molecular weight glycoprotein per particle - apolipoprotein (a) [(apo(a)], a plasminogen homologue.

The apo(a) component clearly distinguishes the Lp(a) particle from LDL and may be responsible for characteristic Lp(a) functions.

As a collaboration between the Centre for Protein Research (University of Otago), the laboratory of Associate Professor Sally McCormick (Biochemistry, University of Otago) and Associate Professor Michael Williams (Cardiology Department, Dunedin Hospital) we will conduct a proteomics approach of Lp(a)-associated proteins that will allow a functional classification of proteins potentially involved in Lp(a) pathogenicity.

We hypothesizes that apo(a), due to its plasminogen homology, is interacting with specific plasma components which are responsible for pro-thrombotic and atherogenic characteristics of Lp(a).

Interesting protein candidates identified by the proteomics approach will be used as targets for absolute protein quantification by mass spectrometry.

This will establish a quantitative signature of proteins associated with Lp(a) and allow us to quantitatively compare the profile of Lp(a)-associated proteins between individuals with low and high Lp(a) plasma levels and those with CVD conditions.

In the long term this research will provide a better understanding of the physiology and pathogenicity of Lp(a) and may help to develop diagnostic tools to estimate the Lp(a) dependent risk factor for developing CVD.