High Density Lipoprotein: Assembly, Structure, Cargo, and Functions

Cardiovascular disease (CVD) is the leading cause of death globally. For close to four decades, we have known that high density lipoprotein (HDL) levels are inversely correlated with the risk of CVD. HDL is a complex particle that consists of proteins, phospholipids, and cholesterol and has the ability to carry micro-RNAs. HDL is constantly undergoing remodelling throughout its life-span and carries out many functions. This review summarizes many of the different aspects of HDL from its assembly, the receptors it interacts with, along with the functions it performs and how it can be altered in disease. While HDL is a key cholesterol efflux particle, this review highlights the many other important functions of HDL in the innate immune system and details the potential therapeutic uses of HDL outside of CVD. 1. Introduction Cardiovascular disease (CVD) remains the dominant cause of death globally [1], and while it is recognized as a multifactorial disease with many risk factors, atherosclerosis is responsible for the major pathology contributing to end stage heart disease [2]. Dyslipidemia, or the imbalance of plasma lipid levels, together with disturbances of intracellular lipid metabolism, underlie atherosclerotic plaque development. Such dyslipidemias include increases in both plasma total and low density lipoprotein (LDL) cholesterol leading to LDL modification and increased accumulation of modified LDL in the intima of the vasculature. Alternatively and perhaps more strikingly is the highly robust inverse correlation between high density lipoprotein (HDL) levels and the risk of CVD, independent of plasma LDL levels [3]. We have now come to understand that for every 5？mg/dL decease in HDL levels below the average (~50？mg/dL), there is an approximate 25% increase in the risk of myocardial infarction [3]. However, while plasma HDL levels offer prognostic value, the genetics behind differing HDL levels have failed to show association between increased HDL levels and protection from myocardial infarction [4]. Given the complex interactions of HDL genetics, function, and interplay with CVD, understanding how HDL modulates cholesterol flux is of increasing significance. Perhaps the most seminal finding of recent times relating to this is the work from Dr. Rader’s laboratory which clearly showed that HDL function (i.e., the ability to promote cholesterol efflux from a standardized cell model) was impaired from patients with CVD and was a leading predictor of risk [5]. Thus, it is imperative that HDL composition and function in normal and disease states is