Further evidence that high-density lipoprotein is a chameleon-like lipoprotein

Zewinger et al. studied 3310 patients undergoing coronary angiography in the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study and determined that serum amyloid A (SAA) concentrations predicted all-cause and cardiovascular mortality. Patients with low SAA levels and higher high-density lipoprotein (HDL) cholesterol levels had lower all-cause and cardiovascular mortality. In contrast, patients with high SAA levels and higher HDL cholesterol levels had increased all-cause and cardiovascular mortality. The authors derived a formula to calculate the levels of biologically ‘effective’ HDL cholesterol based on SAA and HDL cholesterol data from the LURIC Study. They validated this approach using two other populations, one with high SAA levels and very high risk for cardiovascular events: 1255 participants with type 2 diabetes on haemodialysis in the German Diabetes and Dialysis Study (4D) and a population-based survey of inhabitants of Augsburg, Germany (KORA S4 Study). In the KORA S4 Study, 4261 participants were recruited; subjects with previous myocardial infarction (n 1⁄4 77), stroke (n 1⁄4 48) or with missing values for HDL cholesterol or SAA were excluded (n 1⁄4 102) as well as those lost to follow-up (n 1⁄4 7). In these populations, HDL cholesterol levels did not predict outcomes, but higher levels of the calculated biologically ‘effective’ HDL cholesterol were associated with reduced risk for all-cause mortality as well as reduced cardiovascular endpoints. In vitro studies showed that SAA-supplemented HDL reduced endothelial nitric oxide (NO) production and increased endothelial production of reactive oxygen species, leading to the loss of the ability of the HDL to decrease adhesion of mononuclear cells to TNF-a-treated endothelial cells. The authors concluded that ‘SAA turned HDL into a pro-inflammatory particle’. In 1994, Liao et al. demonstrated that mildly oxidized lowdensity lipoprotein (LDL), which has been implicated in the development of atherosclerosis dramatically induced hepatic mRNA levels for inflammatory isotypes of SAA in mice genetically susceptible to develop atherosclerosis, but not in mice genetically resistant to atherosclerosis. In 1995, Van Lenten et al. reported that anti-inflammatory HDL became pro-inflammatory during the acute phase response in both rabbits and humans. The acute phase response in rabbits was accompanied by high levels of SAA that displaced the main protein in HDL apolipoprotein A-I (apoA-I). In contrast to normal HDL, which was anti-inflammatory based on in vitro assays, the SAA-enriched HDL was pro-inflammatory. Moreover, SAA levels significantly correlated with the extent of aortic atherosclerosis and with the inflammatory properties of HDL, but not with HDL cholesterol levels. The main protein in LDL is apoB, a protein that does not exchange between particles. The main protein in HDL is apoA-I, which readily moves between particles. Indeed, all proteins associated with HDL are continuously moving on and off the HDL particles. It was hypothesized that HDL is a shuttle whose size is estimated by measurement of HDL cholesterol, but the contents of the shuttle are not described by this measurement. It was also hypothesized that HDL evolved as part of the innate immune system and is a chameleon-like lipoprotein. In the absence of an acute phase response or systemic inflammation, the proteins associated with HDL are anti-inflammatory. However, in the presence of an acute phase response, or in the presence of systemic inflammation, the proteins associated with HDL are pro-inflammatory. Thus HDL can be thought of as an amplification system, enhancing inflammation in the presence of an acute phase response or in the presence of systemic inflammation, but which promotes the maintenance of an anti-inflammatory state in the absence of an acute phase response or systemic inflammation. Consistent with this hypothesis, Ansell et al. reported that subjects with high levels of HDL cholesterol with coronary heart disease had pro-inflammatory HDL, while normal subjects had anti-inflammatory HDL. Besler et al. demonstrated that HDL