Intracellular tPA–PAI-1 interaction determines VLDL assembly in hepatocytes
Wen Dai, Heng Zhang, Hayley Lund, Ziyu Zhang, Mark Castleberry, Maya Rodriguez, George Kuriakose, Sweta Gupta, Magdalena Lewandowska, Hayley R. Powers, Swati Valmiki, Jieqing Zhu, Amy D. Shapiro, M. Mahmood Hussain, José A. López, Mary G. Sorci‐Thomas, Roy L. Silverstein, Henry N. Ginsberg, Daisy Sahoo, Ira Tabas, Ze Zheng
Abstract
Apolipoprotein B (apoB)-lipoproteins initiate and promote atherosclerotic cardiovascular disease. Plasma tissue plasminogen activator (tPA) activity is negatively associated with atherogenic apoB-lipoprotein cholesterol levels in humans, but the mechanisms are unknown. We found that tPA, partially through the lysine-binding site on its Kringle 2 domain, binds to the N terminus of apoB, blocking the interaction between apoB and microsomal triglyceride transfer protein (MTP) in hepatocytes, thereby reducing very-low-density lipoprotein (VLDL) assembly and plasma apoB-lipoprotein cholesterol levels. Plasminogen activator inhibitor 1 (PAI-1) sequesters tPA away from apoB and increases VLDL assembly. Humans with PAI-1 deficiency have smaller VLDL particles and lower plasma levels of apoB-lipoprotein cholesterol. These results suggest a mechanism that fine-tunes VLDL assembly by intracellular interactions among tPA, PAI-1, and apoB in hepatocytes.