Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat

Abstract

The mechanisms for the association of old age with post-prandial hyperlipidemia and atherosclerosis are not well understood. Post-prandial hyperlipidemia has emerged as a significant risk for atherosclerosis. The liver is the central organ for lipoprotein metabolism. The initial step in the hepatic uptake of post-prandial lipoproteins is their transfer from the hepatic sinusoidal capillary lumen across the hepatic sinusoidal endothelium into the space of Disse. Here, they access hepatocytes for receptor-mediated uptake. We proposed that fenestrations (pores) within the hepatic sinusoidal endothelium filter lipoproteins on the basis of size. Recently we discovered age-related changes in the sinusoidal endothelium (pseudocapillarization), including reduction in the porosity of the endothelium. Using the impulse response technique in perfused rat livers, we found that aging is associated with impaired hepatic transendothelial transfer of chylomicrons with diameters smaller than those of fenestrations. In conclusion, age-related pseudocapillarization of the hepatic sinusoidal endothelium provides a novel mechanism for the association of old age with impaired hepatic lipoprotein metabolism and with atherosclerosis.

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

“…Das et al showed that nine months was required before overt liver injury was observed in response to high levels of arsenic and that this injury was associated with increased oxidative damage and cytokine release (Das et al, 2005). Capillarization has been shown to occur with aging, an effect that may be caused by progressive oxidative injury to LSEC (Hilmer et al, 2005;Cogger et al, 2004). The data in Fig.…”

“…Liver angiogenesis in general is recognized as an important factor in the pathogenesis not only for portal fibrosis, but also for portal hypertension and progression of hepatocellular carcinomas (Tsuneyama et al, 2003;Ward et al, 2004;Semela et al, 2004;Moreau, 2005;Fernandez et al, 2005). Finally, liver capillarization impacts the systemic vasculature by decreasing liver metabolism of lipids, lipoproteins, and glucose to promote atherogenesis in response to environmental stresses and aging (Braet et al, 2002;Cogger et al, 2004;Hilmer et al, 2005).…”

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%.…”

“…Lipoproteins of an average diameter of 56 nm freely cross the liver endothelium in young rats. However, defenestration associated with old age [9] and treatment with a surfactant, poloxamer 407 [27], are associated with impaired transfer of lipoproteins and hypertriacylglycerolaemia. Delayed chylomicron remnant clearance and subsequent post-prandial hypertriacylglycerolaemia are features of type 1 diabetes [10][11][12]; thus it is possible that the substantial loss of fenestrations may contribute to this dyslipidaemia.…”

“…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]. This provides a mechanism for age-related impairment in chylomicron remnant clearance and post-prandial hypertriacylglycerolaemia, thus possibly contributing to enhanced vascular risk among older people [4].…”