Friend Turns Foe: Transformation of Anti-Inflammatory HDL to Proinflammatory HDL during Acute-Phase Response

Abstract

High-density lipoprotein (HDL) is a major carrier of cholesterol in the blood. Unlike other lipoproteins, physiological functions of HDL influence the cardiovascular system in favorable ways except when HDL is modified pathologically. The cardioprotective mechanism of HDL is mainly based on reverse cholesterol transport, but there has been an emerging interest in the anti-inflammatory and antioxidant roles of HDL. These latter activities of HDL are compromised in many pathological states associated with inflammation. Further, abnormal HDL can become proinflammatory contributing to oxidative damage. In this paper, we discuss the functional heterogeneity of HDL, how alterations in these particles in inflammatory states result in loss of both antioxidant activity and reverse cholesterol transport in relation to atherosclerosis, and the need for assays to predict its functionality.

Figure 1

An overview of reverse cholesterol transport. HDL promotes the process of reverse cholesterol transport, whereby excess cholesterol present in the macrophage is effluxed to HDL and ultimately delivered to liver for excretion. HDL: high-density lipoprotein; CE: cholesterol ester; FC: free cholesterol; Apo A-I: apolipoprotein A-I; ABCA1: adenosine triphosphate-binding cassette transporter A1; LCAT: lecithin cholesterol acyltransferase; CETP: cholesterol ester transfer protein; PLTP: phospholipid transfer protein; LDL: low-density lipoprotein; LDL-R: low-density lipoprotein receptor; SR-BI: scavenger receptor class B-type I; VLDL: very low-density lipoprotein; TGL: triglycerides.

Figure 2

Model of bidirectional conversion of HDL from anti-inflammatory to proinflammatory. Normal anti-inflammatory HDLs are rich in apolipoproteins (ovals) and antioxidant enzymes (squares). After exposure to pro-oxidants, oxidized lipids, and proteases, proinflammatory HDLs have less lipoprotein and the major transporter apolipoprotein A-I are disabled by the addition of chlorine, nitrogen, and oxygen to protein moieties. PON1 cannot exert its antioxidant enzyme activity as Apo A-I can no longer stabilize it. In addition, pro-oxidant acute-phase proteins are added to the particle (serum amyloid A (SAA) and ceruloplasmin). “Apo A-I ↑”, “PON1 ↑” indicates that the number of respective molecules present in anti-inflammatory HDL is more when compared to that of proinflammatory HDL. Apo J: apolipoprotein J; CE: cholesterol ester; PON1: paraoxonase-1; GSH: glutathione; SAA: serum amyloid A; Apo A-I: apolipoprotein A-I; Apo-AII: apolipoprotein A-II; LCAT: lecithin cholesterol acyltransferase; PAF-AH: platelet-activating acyl hydrolase.