Lipoproteins and the liver sieve: The role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis

Abstract

The liver sieve, formed by the fenestrated hepatic sinusoidal endothelium, is a dynamic biofilter separating the hepatic blood from the plasma within the space of Disse. It filters macromolecules of differing sizes, especially lipoproteins. More specifically, it acts as a barrier to the large triglyceride-rich parent chylomicrons, while permitting the smaller triglyceride-depleted but cholesterol- and retinol-rich remnants to enter the space of Disse. There the remnants contact specific receptor sites on the hepatocyte microvilli. Thus, the liver sieve is the first site of hepatic selection and consequent metabolism of dietary cholesterol and fat-soluble vitamins, as well as rejection of dietary triglycerides. Therefore, perturbations of the porosity of the sieve, whether from changes in size, number of fenestrae, or composition of the underlying extracellular matrix within the space of Disse, will have a profound influence on the metabolism of lipoproteins. This disturbance of the homeostasis of lipids, including fat-soluble vitamins and cholesterol, as well as other macromolecules, may tilt the balance between health and disease in a variety of organs and tissues, such as the liver, kidney and arteries.

Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid

“…Furthermore, it provides one mechanism for the effects of CR on lipids and vascular disease. One of the most important functions of fenestrations appears to be related to the transfer of chylomicrons remnants across the endothelium for subsequent hepatic metabolism (Fraser et al, 1995). This transfer of lipoproteins is impaired in old age .…”

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

“…In this study we focussed on the effects of diabetes on the LSECs because recent reports indicate an association between pathological changes in the LSECs and dyslipidaemia [2,4,9]. In the diabetic livers, the LSECs were found to be about 40% thicker and the porosity of fenestrations was reduced by about 50%.…”

“…This has potential implications for liver function, particularly the hepatic clearance of lipoproteins such as chylomicron remnants [2]. One of the initial steps in the metabolism of lipoproteins is that chylomicron remnants pass through fenestrations into the space of Disse for receptor-mediated uptake and subsequent processing in hepatocytes.…”

“…The hepatic microvasculature consists of sinusoids, which are porous, gossamer-like vessels that connect afferent portal triads to exiting central hepatic venules over a distance of about 1 mm. Approximately one billion sinusoids form the rich capillary network of the liver, which permits the vast hepatic blood flow to course slowly and intimately between the cords of hepatocytes [2,3].…”

“…The cytoplasmic extensions of LSECs are extremely thin (100-200 nm), which also promotes the transport of smaller, diffusible substrates [3]. Of interest in diabetes mellitus is the observation that fenestrations in the LSECs appear to act as conduits for the transfer of some lipoproteins, especially chylomicron remnants, between the blood and hepatocytes [2,4]. In old age, a substantial loss of fenestrations in the LSECs occurs [5][6][7][8], which impairs lipoprotein transfer to the hepatocyte [9].…”