High-Density Lipoprotein Attenuates Inflammation and Coagulation Response on Endotoxin Challenge in Humans

Abstract

Objective-Low high-density lipoprotein (HDL) cholesterol is a strong independent cardiovascular risk factor, which has been attributed to its role in reverse cholesterol transport. Whereas HDL also has potent antiinflammatory effects, the relevance of this property remains to be established in humans. In the present study, we evaluated whether there is a relation between HDL and sensitivity toward a low-dose endotoxin challenge. Methods and Results-Thirteen healthy men with genetically determined isolated low HDL cholesterol (averaging 0.7Ϯ0.1 mmol/L) and 14 age-and body weight-matched healthy men with normal/high HDL cholesterol levels (1.9Ϯ0.4 mmol/L) were challenged with low-dose endotoxin intravenously (1 ng/kg body weight). The incidence and severity of endotoxin-associated clinical symptoms was increased in the low HDL group. Accordingly, both the inflammatory response (tumor necrosis factor-␣, IL-1␤, IL-6, IL-8, and monocyte chemoattractant protein-1) as well as thrombin generation (prothrombin activation fragments F 1ϩ2 ) were significantly increased in the low HDL group on endotoxin challenge. A fter the first report on the potential antiatherogenic effect of high-density lipoprotein (HDL) almost 60 years ago, HDL is now generally acknowledged as a potent antiatherogenic mediator. 1 The impact of isolated low HDL cholesterol on atherogenesis was recently underscored by the finding that carotid intima-media thickness in patients with genetically determined low apolipoprotein (apo) A-I was comparable to that in patients with familial hypercholesterolemia. 2 In line, HDL increasing drugs now are prime candidates for combined use with statins in high-risk subjects. Conclusions-LowTraditionally, the protective effect of HDL was considered to be confined to its role in the reverse cholesterol transport pathway. However, recent evidence supports a wide array of antiatherogenic effects by HDL, comprising antioxidative, antithrombotic, and antiinflammatory effects. 3 The latter has attracted special interest, because inflammation has been acknowledged to underlie atherosclerotic lesion formation. At the same time, HDL cholesterol consistently shows an inverse relation with systemic markers of inflammation. 4 Interestingly, HDL-increasing compounds (eg, reconstituted HDL) have recently been shown to attenuate systemic inflammation in humans, 5 as well as vessel wall inflammation in experimental animal models. 6 However, it remains to be established whether HDL also exerts antiinflammatory effects in the human setting. In the present study, we evaluated the impact of plasma HDL cholesterol level on the sensitivity toward a low-dose endotoxin challenge in subjects with genetically determined low versus normal/high HDL cholesterol levels. Patients and Methods Study ParticipantsStudy subjects were recruited from a study designed to identify genes that control HDL cholesterol levels. 2 Healthy male subjects with plasma HDL cholesterol levels Ͻ10 th percentile (low HDL group, nϭ13) and healthy male subjects with plasma...

Functionality of HDL: Antioxidation and Detoxifying Effects

“…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).…”

Associação entre marcadores inflamatórios e fatores de risco cardiovascular em mulheres de Kolkata, W.B, Índia

“…In addition, there was an inverse association between WBC count and HDL-C. HDL cholesterol has consistently shown an inverse association with systemic markers of inflammation in many prospective studies 5,24,28 . A recent study by Birjmohun et al 29 have demonstrated that apparently healthy individuals with genetically determined isolated low HDL-C levels are more susceptible to low-dose endotoxin challenge in comparison with subjects with normal or high HDL-cholesterol levels. The study revealed a strong inverse association between HDL-C and apo A-1 levels versus leukocyte response and plasma CRP levels, supporting an antiinflammatory effect of HDL-C.…”

HDL in Infectious Diseases and Sepsis

“…Low HDL-C levels inversely correlate with the severity of septic disease and associate with an exaggerated systemic inflammatory response (Wendel et al 2007), although it is difficult to establish whether changes in plasma lipoproteins simply reflect the severity of disease or they can directly modify the host response to inflammation. Also in healthy subjects low HDL levels are associated with increased inflammatory response on endotoxin challenge compared to subjects with normal or high HDL levels (Birjmohun et al 2007), without differences in the HDL proteome (Levels et al 2011). These observations indicate a positive role of HDL in the protection against sepsis.…”