Sphingomyelin in high-density lipoproteins: structural role and biological function

Abstract

High-density lipoprotein (HDL) levels are an inverse risk factor for cardiovascular diseases, and sphingomyelin (SM) is the second most abundant phospholipid component and the major sphingolipid in HDL. Considering the marked presence of SM, the present review has focused on the current knowledge about this phospholipid by addressing its variable distribution among HDL lipoparticles, how they acquire this phospholipid, and the important role that SM plays in regulating their fluidity and cholesterol efflux from different cells. In addition, plasma enzymes involved in HDL metabolism such as lecithin-cholesterol acyltransferase or phospholipid transfer protein are inhibited by HDL SM content. Likewise, HDL SM levels are influenced by dietary maneuvers (source of protein or fat), drugs (statins or diuretics) and modified in diseases such as diabetes, renal failure or Niemann-Pick disease. Furthermore, increased levels of HDL SM have been shown to be an inverse risk factor for coronary heart disease. The complexity of SM species, described using new lipidomic methodologies, and their distribution in different HDL particles under many experimental conditions are promising avenues for further research in the future.

Figure 1

Different molecules of sphingomyelin according to the length and unsaturation of the acyl residue and sphingoid. A, fatty acid compositions of sphingomyelin species (yellow box) and A and B, long-chain base compositions of sphingomyelins (blue box). Note that the major difference among SM molecules is length and saturation of fatty acids. (http://www.lipidmaps.org/data/structure/LMSDSearch.php?Mode=ProcessClassSearch&LMID=LMSP0301&s=sphingomyelin).

Figure 2

Flow chart displaying the stages used to select the references considered. The present report has adhered to systematic review guidelines [14]. A search in Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/) using the keywords “high-density lipoprotein and sphingomyelin,” “sphingomyelin and diet,” “sphingomyelin and drugs,” “plasma and sphingomyelin,” identified 3,389 hits from November 1945 to March 2013. Documents that failed to meet the criteria shown were discarded. Thus, this review covers the works related to sphingomyelin and HDL in 181 papers. EndNote X1 (Bld 2566, Thomson Reuters: New York, NY, USA, 2007).

Figure 3

Location of SM and other surface components of HDL. Phosphate choline groups of sphingomyelin on the surface are depicted close to cholesterol molecules in a HDL lipoparticle.

Figure 4

Current model of SM on cholesterol efflux. SM both in HDL and cell membrane regulates ATP binding cassette proteins implicated in reverse cholesterol transport. Cellular SM has been described as a stimulant of SM and cholesterol efflux through ABCG1, ATP-binding cassette transporter G1 [92]. On the other hand, cell membrane SM inhibits ABCA1, ATP-binding cassette transporter A1 activity [102], while SM present in HDL stimulates activity of this transporter [103].

Figure 5

Role of HDL-SM in modulating enzymes of HDL metabolism. SM and cholesterol have been described as inhibitors of PLTP, phospholipid transfer protein. SM has been also described as inhibitor of GVSPLA₂, group V secretory phospholipase A₂, LPL, lipoprotein lipase and LCAT enzymes [,–111].

Figure 6

Influence of SM in delivering cholesterol to cells through the SR-BI receptor. SR-BI mediates cholesterol ester influx by the cells but also bidirectional flux of unesterified cholesterol and phospholipids between HDL and cells. Both cell membrane and HDL SM inhibit SR-BI transport activity, while HDL PC stimulates its transport activity [31,121,122].