A Feedback Regulatory Pathway Between LDL and alpha(1)Proteinase Inhibitor in Chronic Inflammation and Infection

作者：Bristow Cynthia L^*; Modarresi Rozbeh; Babayeva Mariya A; LaBrunda Michelle; Mukhtarzad Roya; Trucy Maylis; Franklin Aaron; Reeves Rudy E R; Long Allegra; Mullen Michael P; Cortes Jose; Winston Ronald

来源：Discovery Medicine, 2013, 16(89): 201-218.

Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being alpha(1)proteinase inhibitor (alpha 1PI, alpha(1)antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4(+) T cells and active alpha 1PI and high levels of inactivated alpha 1PI. By inducing LDL-RFMs-mediated cellular locomotion, active alpha 1PI regulates the number of CD4(+) T cells. We sought to investigate whether CD4(+) T cells and alpha 1PI directly impact lipoprotein levels. At the cellular level, we show that active alpha 1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active alpha 1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P%26lt;0.001) and that therapeutic, weekly infusions of active alpha 1PI elevate the number of CD4(+) T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of alpha 1PI and CD4(+) T cells in HIV-1 disease, we reveal that LDL and alpha 1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive alpha 1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for alpha 1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport.

• 出版日期2013-11