Hepatic pseudocapillarisation and atherosclerosis in ageing

Couteur, David G. Le; Fraser, Robin; Cogger, Victoria C.; McLean, Allan J.

doi:10.1016/s0140-6736(02)08524-0

Cited by 133 publications

(112 citation statements)

References 25 publications

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“…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%.…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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]. As such, there are potential parallels with dyslipidaemia in patients with diabetes mellitus [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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Aims/hypothesis Diabetes mellitus is associated with extensive vascular pathology, yet little is known about its longterm effects on liver sinusoidal endothelial cells (LSECs).Potential diabetic changes in LSECs are important because of the role played by fenestrations in the LSECs in hepatic disposition of lipoproteins. Materials and methods Surgical liver biopsies for electron microscopy and immunohistochemistry were obtained from baboons with long-standing streptozotocin-induced, insulin-treated diabetes mellitus and compared with those from age-matched control animals. Results There was an increase in the thickness of LSECs (170±17 vs 123±10 nm, p<0.01). Fenestrations in LSECs, as determined by overall porosity, were markedly reduced (1.4±0.1% vs 2.6±0.2%, p<0.01). Increased numbers of stellate cells were seen on electron microscopy, and this finding was corroborated by increased smooth muscle actin expression. Diabetes mellitus was also associated with increased endothelial production of von Willebrand factor and caveolin-1. Conclusions/interpretation Diabetes mellitus in the nonhuman primate is associated with marked changes in LSECs, including a reduction in fenestrations. Such changes provide an additional and novel mechanism for impaired hepatic lipoprotein clearance and post-prandial hyperlipidaemia in diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…The reason(s) for this age related reduction in hepatic blood flow remains unknown and is puzzling since it has been concluded that there are few significant structural or biochemical changes in the aging liver (Jansen, 2002;Popper, 1986). More recently, however, Le Couteur et al (LeCouteur et al, 2001) have reported that in rats there are significant age associated reductions in the fenestration of liver sinusoidal endothelial cells (LSECs), increased expression of von Willebrand's factor, and increased deposition of extracellular matrix, basal lamina, and connective tissue elements in the Space of Disse leading to early capillarization or "pseudocapillarization" of the sinusoids in rats (LeCouteur et al, 2002). The same group has shown similar age-related alterations in LSEC in mice (Warren et al, 2005), baboons and humans .…”

Section: Introductionmentioning

confidence: 99%

Age-related changes in the hepatic microcirculation in mice

Yoshiya

Sørensen

Bethea

et al. 2007

Experimental Gerontology

113

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Aging of the liver is associated with impaired metabolism of drugs, adverse drug interactions, and susceptibility to toxins. Since reduced hepatic blood flow is suspected to contribute this impairment, we examined age-related alterations in hepatic microcirculation.. Livers of C57Bl/6 mice were examined at 0.8 (pre-pubertal), 3 (young adult), 14 (middle-aged) and 27 (senescent) months of age using in vivo and electron microscopic methods. The results demonstrated a 14% reduction in the numbers of perfused sinusoids between 0.8 and 27 month mice associated with 35% reduction in sinusoidal blood flow. This was accompanied by an inflammatory response evidenced by a 5-fold increase in leukocyte adhesion in 27 month mice, up-regulated expression of ICAM-1, and increases in intrahepatic macrophages. Sinusoidal diameter decreased 6-10%. Liver sinusoidal endothelial cell (LSEC) dysfunction was seen as early as 14 months when there was a 3-fold increase in the numbers of swollen LSEC. The endocytotic capacity of LSEC also was found to be reduced in older animals. The sinusoidal endothelium in 27 month old mice exhibited pseudocapillarization. In conclusion, the results suggest that leukocyte accumulation in the sinusoids and narrowing of sinusoidal lumens due to pseudocapillarization and dysfunction of LSEC reduce sinusoidal blood flow in aged livers.

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“…Transmission electron microscopy (TEM) has contributed considerably to liver research [1][2][3][4][5][6][7][8][9][10] after the introduction of perfusion fixation, with glutaraldehyde fixative through the portal vein. A clear distinction of sinusoidal endothelial, Kupffer, pit, and stellate cells became apparent, including details such as the endothelial fenestrae.…”

Section: Jet-fixation: a Novel Methods To Improve Microscopy Of Human mentioning

confidence: 99%

Jet-fixation: A novel method to improve microscopy of human liver needle biopsies

et al. 2013

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example, hepatocellular carcinoma). In this regard, we did not exclude patients with high MELD (range in our study 5 to 28) nor did we omit patients with renal insufficiency. This allowed a clear and unbiased evaluation of feasibility, efficacy, and safety of the intervention in a broad range of a homogenous group of patients. Based on this uncensored approach, we were able to perform uni-and multivariate analysis in a large enough population and make an estimate of the ideal cutoff point of the MELD score, which was retained as one of the predictive factors of recurrence of encephalopathy.Third, our series also comprised sufficient follow-up to appreciate the long-term effect of intervention (overall follow-up in our series postembolization: 697 6 157 days).Overall, we appreciate that Singh et al. have substantiated our findings, namely, that embolization of large spontaneous portosystemic shunts for a refractory condition is feasible, safe, and effective. On the other hand, one should keep in mind that embolization of large spontaneous portosystemic shunts for a refractory condition should be reserved for a group of well-selected patients with sufficient critical functional liver mass (indirectly reflected by a MELD score 11) and should be done by a team with substantial experience to perform and manage these kinds of procedures.

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Hepatic pseudocapillarisation and atherosclerosis in ageing

Cited by 133 publications

References 25 publications

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

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

Age-related changes in the hepatic microcirculation in mice

Jet-fixation: A novel method to improve microscopy of human liver needle biopsies

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