The liver carries out numerous separate metabolic and detoxification functions which are essential for maintaining human health. Supporting these functions are the dense networks of blood vessels called sinusoids and the highly specialised liver sinusoidal endothelial cells (LSEC) that line these vessels.
The LSEC occupies a strategic position in the liver, separating blood in the sinusoid from the surrounding liver cells. It has long been recognized that LSECs have a role facilitating, and perhaps regulating, the transfer of substrates between the blood and the liver parenchyma, forming a blood-liver cell barrier. LSECs have a unique morphology compared to other endothelial cells, which underpin their physiological role in substrate transfer. The cytoplasmic extensions of LSECs are very thin and perforated with transcellular holes called fenestrations that are true discontinuities in the endothelium. These fenestrations permit the bidirectional transfer of a wide range of substrates between the blood and underlying liver cells for further processing. These substrates include plasma and substances within plasma, such as medications, toxins, albumin, smaller lipoproteins, colloidal particles and importantly insulin. The fenestrated LSEC acts as a filter for larger particles and hence has been termed ‘the liver sieve’.
We have recently explored the role of the LSEC in hepatic insulin metabolism and found the initial transfer through the fenestrations to be critical in liver insulin signalling and metabolism. This key step is especially important in the context of the numerous diseases and pathological processes that influence fenestrations, including: liver disease, exposure to liver toxins and most significantly, ageing.