Poloxamer 407 is a ubiquitous synthetic surfactant that causes massive hyperlipidemia and atherosclerosis in the rodent. The initial step in hepatic metabolism of lipoproteins is their transfer through 100-200 nm pores (fenestrations) in the liver sinusoidal endothelial cell, prior to receptor-mediated uptake. The 'liver sieve hypothesis' emphasizes the role of these fenestrations in the regulation of lipoprotein disposition. Here we show that P407 causes dramatic defenestration of the liver sinusoidal endothelium in vivo. By 24h after intraperitoneal administration in mice, fenestrations were reduced by approximately 80% coincident with a 10-fold increase in plasma lipids. Moreover impulse-response experiments in the perfused rat liver showed that P407 prevented the passage of small chylomicrons across the liver sinusoidal endothelium. Defenestration was also induced acutely with P407 in isolated liver sinusoidal endothelial cells, indicating this is a direct effect of P407 on fenestrations. The results establish the role of the porosity of the liver sinusoidal endothelial cell as a pivotal yet relatively unrecognised mechanism for hyperlipidemia. Furthermore, the results establish an intriguing mechanism for surfactant-induced hyperlipidemia. Thus the liver sieve is a new and untapped target for the treatment and prevention of hyperlipidemia.