High-Density Lipoproteins, Environmental Pathogens and Toxins

In recent studies, the molecular composition of the HDL particle has been assigned significant, functional importance (Besler et al. 2012), which is of particular relevance with respect to reported changes in HDL composition in disease. Interestingly, alterations in HDL composition have also been observed in man during endotoxemia (Levels et al. 2011) and in endotoxin-treated mice (Chiba et al. 2011). As suggested above, data indicate that HDL has an important role in neutralising and detoxifying invading pathogens to prevent systemic inflammatory responses or sepsis, which is the leading cause of death in intensive care units (ICUs) of highincome countries (Levels et al. 2011; Russell 2006). Concurrently, the interaction of HDL with viruses, parasites and environmental toxins has also been a focus of recent interest. This is reflected in reviews of the impact of gram-positive and gramnegative bacterial toxins in sepsis (Ramachandran 2013), the role of HDL in innate immunity (Feingold and Grunfeld 2011) and the immune system (Kaji 2013) and xenobiotic metabolism, disposition and regulation of receptors (Omiecinski et al. 2011) to which the reader is referred. In this chapter, the role(s) of HDL as a detoxifying agent during exposure to different environmental pathogens or toxins will be discussed.

Bacterial Pathogens

Multiple alterations in lipid and lipoprotein metabolism occur during the acute phase response. Within HDL, apoA-I, cholesterol and phospholipid levels decrease, as do certain enzyme activities, e.g. PON1 (Khovidhunkit et al. 2004), whilst free apoA-I (Cabana et al. 1997) and triglyceride levels increase (Cabana et al. 1996). As a consequence, reverse cholesterol transport decreases, accompanied by increased cholesterol delivery to immune cells. Such alterations initially protect the host from the harmful effects of invading pathogens but will contribute to atherogenesis if prolonged (Khovidhunkit et al. 2004).

A crucial factor in the detoxifying properties attributed to HDL is the ability to neutralise the invading pathogen. A number of human studies have shown that circulating lipoproteins, principally HDL, are able to bind lipopolysaccharides (LPS) from gram-negative bacteria as well as lipoteichoic acid (LTA) from grampositive bacteria (Khovidhunkit et al. 2004; Levels et al. 2003, 2011). Binding to HDL inhibits LPS interaction with cell surface toll-like receptor 4 (TLR-4) (Underhill and Ozinsky 2002) and LTA interaction with TLR-2 (Flo et al. 2000), receptors known to mediate inflammatory responses (macrophage activation, cytokine release). These neutralising effects of HDL have been confirmed in humans with low HDL levels who show a more robust inflammatory response to LPS administration (Birjmohun et al. 2007).

During the acute phase response, HDL protein and lipid compositions change (Khovidhunkit et al. 2004). Observations indicate that apoA-I can be replaced by the positive acute phase protein SAA (Artl et al. 2000). SAA is able to influence HDL-mediated cholesterol metabolism through its inhibitory effects on SR-BImediated selective cholesterol uptake (Cai et al. 2005). It has recently been suggested to facilitate the binding of HDL, isolated from mice injected with LPS, to vascular proteoglycans (Chiba et al. 2011). The relevance of these observations is important when taken together with the up to 1,000-fold increase in concentrations of plasma SAA during acute phase reactions such as inflammation or infection. In addition, several isoforms of SAA, still with unknown functions, have recently been detected in acute phase HDL (Levels et al. 2011).

The neutralising effects of HDL during LPS exposure are dependent on phospholipids as well as proteins. ApoA-I is suggested to be the major neutralising factor (Massamiri et al. 1997). Thus, direct interaction between LPS and the C-terminus of apoA-I can decrease TNF-α release from macrophages in vitro (Henning et al. 2011). The role of apoA-I as a neutralising agent is further strengthened by the beneficial effects of apoA-I on LPS-induced acute lung injury and endotoxemia, as shown in mice (Yan et al. 2006).

The HDL receptor, SR-BI, is highly expressed in hepatocytes and steroidproducing cells and has an important role regarding the fate of the neutralised pathogens. In mice, it is suggested to protect against endotoxemia through its roles in facilitating glucocorticoid production as well as hepatic clearance of LPS. In this respect, SR-BI has been suggested to mediate the binding and uptake of LPS as well as LTA (Vishnyakova et al. 2006). Additionally, an alternatively spliced variant, SR-BII, has been shown to bind directly a variety of bacteria suggesting a conserved role of these receptors in pattern recognition and innate immunity (Webb et al. 1998).