The complexity of high-density lipoproteins.

In a 1984 review, Shlomo Eisenberg1 wrote, “In spite of their large number in plasma, it is difficult to define HDL as a vehicle for lipid transport ... other considerations must apply to this lipoprotein.” In this issue of Circulation, Suzuki et al2 report that high-density lipoprotein (HDL) suppresses the type I interferon response in macrophages challenged with lipopolysaccharide. They found that HDL specifically promoted the translocation of TRIF-related adapter molecule (TRAM) into intracellular compartments, leading to impaired signaling by toll receptor 4 (TLR4) and TRIF (Toll/ interleukin-1 receptor domain-containing adaptor protein inducing interferon). In mice lacking apolipoprotein A-I (apoAI), administration of Salmonella typhimurium (which expresses lipopolysaccharide) resulted in 6-fold higher plasma levels of interferon, which is a key regulator of the type I interferon response. These actions of HDL were independent of the interaction of HDL with ATP-binding cassette transporter ABCA1 or ABCG1. These effects of HDL were also independent of the cholesterol content of macrophages and were independent of HDL inhibiting the binding of lipopolysaccharide to CD14 or TLR4 on the cell surface. Therefore, Suzuki et al2 proposed a mechanism of action in which HDL depletes the plasma membrane of TRAM, a key adaptor molecule that activates TRIF in endosomal compartments.