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Liver Sieve - ISCHS

14th International Symposium on Cells of the Hepatic Sinusoids (ISCHS, 2008)
Tromso, Norway, from 31 August to 4 September, 2008

These symposia occur every two years in cities around the world, especially Europe, Japan, USA and the 9th was held in Christchurch, New Zealand.

They focus on the liver sinusoidal endothelial cells (LSEC), the Kupffer cells (hepatic macrophages), and the perisinusoidal stellate cells (retinol storing cells and potential fibroblasts) as well as the ‘pit’ cells (large granular lymphocytes or N.K. cells).

We presented the following review of the importance of the LSEC fenestrations in modulating atherogenesis and lipoprotein metabolism. Our Australian cousins concentrated on the ageing liver with implications not only for death from atherosclerosis, but also for autoimmune disease, diabetes and fibrosis.

The Tromso team is famous for their work on LSEC endocytosis, the largest reticulo-endothelial system (RES) in the body. LSEC scavenging removes and disposes of waste products from the blood, such as peptides, lysomal enzymes and glycosolated proteins. Lactate is released which can be used as energy by the neighbouring hepatocytes. This system is akin to a garbage and recycling plant of a modern city.

Professor Bard Smedsrod extended a warm welcome to hepatophils and it was great chance to visit the very north of Europe, way beyond the Arctic Circle, in the beautiful season of autumn (fall).

We from Otago University (the most southern medical school in the world) were appreciative guests of Univeristy of Tromo (the world's most northern medical school).

The next symposium in August-September 2011 is to be hosted by Professor Tsukamoto of Los Angeles. Email hidekazu.tsukamoto@keck.usc.edu

Robin Fraser

ATHEROSCLEROSIS, LIPOPROTEINS AND THE LIVER SIEVE

Fraser R, Day WA, Dobbs BR, Jamieson HA, Cogger VC, Hilmer SN, Warren A, Le Couteur DG,
University of Otago, Christchurch, New Zealand and University of Sydney, Concord, Australia

Atherosclerosis, localized thickenings or plaques of the intima of arteries from cholesterol deposition and cellular hyperplasia causing thrombosis and obstruction, is a major killer due to ischaemic heart failure, strokes, gangrenous feet and aortic aneurysm. In 1976 in Tokyo, at the third International Symposium on Atherosclerosis, we first presented data confirming that the fenestrated liver sinusoidal endothelial cells (LSEC) filtered chylomicrons and their remnants (intestinal lipoproteins transporting cholesterol) according to their size.1 We postulate, with implications in atherogenesis, that sieving controls the balance between exogenous (dietary) and endogenous (hepatic-synthesized) cholesterol in tandem with hepatocyte receptor-mediated uptake.2

The possibility that the size and composition of chylomicrons influences atherogenesis had long intrigued us.3 Chylomicrons, in cholesterol-fed and atherosclerotic-prone New Zealand white rabbits increased in diameter from about 50-100nm to 100-800 nm as triglycerides were added to the cholesterol in their diet,4 as well as increasing the ratio of free to esters of cholesterol.5 Zilversmit and others have shown chylomicron lipids, especially the esters of cholesterol and retinol are the major lipids in atherosclerotic plaques.6

Despite fat of dietary origin in early fatty plaques, Wissler’s group showed that the concurrent hyperplasia of the arterial smooth muscle cells (SMC), at least in tissue culture, was triggered not by chylomicrons, but by low density lipoproteins transporting liver-synthesized cholesterol.7 It is known that dietary cholesterol, if it enters the hepatocytes, inhibits their synthesis of cholesterol.2

Florén in 1984 demonstrated that in vitro hepatocytes bound chylomicron-cholesterol, but in vivo large native chylomicrons did not bind, this only occurring when smaller chylomicron remnants entered the hepatic circulation. He suggested this was due to “steric hindrance” of chylomicron-uptake.8 Wisse’s seminal hypothesis in 1970, that the 100nm pores or fenestrae of the LSEC might filter chylomicrons, explains this “steric hindrance”.9 In 1978 both our group and Naito and Wisse published to confirm this sieving, as shown by comparing the sizes of chylomicrons in the sinusoidal lumen compared to the space of Disse, as well as the trapping of radio- labeled chylomicrons and remnants of small size within the liver. 10, 11

Since then our major research thrust has been testing the hypothesis that a low porosity liver sieve predisposes to post-prandial hyperlipidaemia (consisting especially of chylomicrons and their remnants, but also of liver synthesized cholesterol in LDL, since the latter’s synthesis would not be switched off by dietary cholesterol2). These experiments confirmed a low porosity in species of high sensitivity to dietary cholesterol (e.g. NZ white rabbits12 and chickens13). In rats and primates with higher porosity sieves, the effects of drugs such as nicotine,14 excess alcohol,15 and various pro-atherogenic-diseases, such as diabetes16a and serotonin 16b which reduce their porosity, lead to hyperlipoproteinaemia. Rabbit sub-species with differing porosities (which were shown to differ in ability to sieve a 70-90nm adenovirus) might in future make interesting experimental subjects if fed cholesterol.17a,b

The new millennium heralded a change of direction, as instigated by our Sydney colleagues with their interest in old age 18. Coronary artery disease and post-prandial hyperlipidaemia increase with age19 and we found that these correlated with a decrease in sinusoidal porosity in many species including humans.20, 21 Whether this decrease is purely an age factor, or is related to long-term diets, toxins or concurrent disease states, has yet to be determined. It has also been shown that the semi-starvation of the Methuselah diet increases porosity and also leads to longevity,22 while some detergents or surfactants decrease porosity and increase atherosclerosis.23

Our dream is to find an enjoyable lifestyle or a safe drug to increase LSEC porosity and longevity24.

References

1. Fraser R, Bosanquet, AG, Day, WA. (1977). Filtration of chylomicrons and their remnants by the liver. In Proceedings of the IVth International Symposium on Atherosclerosis, Tokyo, 1976 in Schettler, F, Goto, Y, Hata, Y, Klose, G Springer-Verlag, Berlin, Heidelberg, New York. pp 256-7.
2. Fraser R, Dobbs BR, Rogers GWT (1995). The role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherogenesis and cirrhosis. Hepatology 21:863-874.
3. Fraser R, Cliff WJ, Courtice FC (1968). The effect of dietary fat load on size and composition of chylomicrons in thoracic duct lymph. Q. Jl. Exp. Physiol. 53:390-8.
4. Fraser R, Courtice FC. (1969). The transport of cholesterol in thoracic duct lymph of animals fed cholesterol with varying triglyceride loads. Aust. J. Exp. Biol. Med. Sci. 47: 723-732.
5. Fraser R (1974). The role of dietary triglycerides in cholesterol metabolism. Atherosclerosis 19:327-336.
6. Zilversmit DB. (1979). Atherogenesis: a post-prandial phenomenon. Circulation 60: 473-485.
7. Fischer-Dzoga K, Fraser R, Wissler RW. (1976). Stimulation of proliferation in stationary primary cultures of monkey and rabbit aortic smooth muscle cell. I. Effects of lipoprotein fractions of hyperlipemic serum and lymph. Exp. Mol. Path. 24:346-359.
8. Florén H. (1984). Binding of apolipoprotein E-rich remnant lipoproteins to human liver membranes. Scand. J. Gastroenterology. 19:473-479.
9. Wisse E. (1970). An electron microscopic study of the fenestrated endothelial lining of the rat liver sinusoids. J. Ultrastruct Res 31:125-150
10. Fraser R, Bosanquet AG, Day WA. (1978). The filtration of chylomicrons by the liver may influence cholesterol metabolism and atherosclerosis. Atherosclerosis 29:113-123.
11. Naito M, Wisse E. (1978). Filtration effect of endothelial fenestrations on chylomicrons transport in neonatal rat liver sinusoids. Cell Tissue Res. 190:371-382.
12. Wright PL, Smith KF, Day WA, Fraser R. (1983). Small liver fenestrae may explain the susceptibility of rabbits to atherosclerosis. Arteriosclerosis 3:344-348.
13. Fraser R, Heslop VR, Murray FEM, Day WA. (1986). Ultrastructural studies of the portal transport of fat in chickens. Br. J. Exp. Path. 67:783-91.
14. Fraser R, Clark SA, Day WA, Murray FEM. (1988). Nicotine decreases the porosity of the rat liver sieve – a possible mechanism for hypercholesterolaemia. Br. J. Exp. Path. 69:345-350.
15. Clark SA, Angus HBA, Cook HB, George PM, Oxner RBG, Fraser R. (1988). Defenestration of the hepatic sinusoids in an alcoholic leads to hyperlipoproteinaemia. Lancet ii:1225-1227.
16. a) Jamieson HA, Cogger VC, Twigg SM, McLennan, SV, Warren A, Cheluvappa R, Hilmer SN, Fraser R, de Cabo R, Le Couteur DG. (2007). Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes. Diabetologia. 50:1969-1976.
    
    b) Wisse E, Van Dierenonck JH, De Zanger RB., Fraser R, McCuskey RS. On the role of the liver endothelial filter in the transport of particulate fat (chylomicrons and their remnants) to parenchymal cells and the influence of certain hormones on the endothelial fenestrae. Communications of Liver Cells. Eds. H Popper, L Bianchi, F Gudat, W Reutter. Proceedings of the 27th Falk Symposium on the occasion of the 5th International Congress of Liver Diseases held at Basel, Switzerland, October 5-7, 1979.g0
17. a) Lievens J, Snoeys J. Vekemans K, Van Linthout S, de Zanger R, Collen D, Wisse E, De Geest B. (2004). The size of sinusoidal fenestrae is a critical determinant of hepatocytes transduction after adenoviral gene transfer. Gene Ther. 11:1523-3.
    
    b) Adams WC, Gaman EM, Feigenbaum SA. (1972) Breed differences in the responses of rabbits to atherogenic diets. Atherosclerosis 16:405-411
18. Le Couteur DG, Fraser R, Cogger VC, McLean AJ, (2002). Hepatic pseudocapillarisation and atherosclerosis in ageing. Lancet 359:1612-1615.
19. Inoue T, Uchida T, Kamishirado H, Takayanagi K, Hayashi T, Morooka S, Saniabadi AR, Nakajima K. (2004). Remnant-like lipoprotein particles as risk factors for coronary artery disease in elderly patients. Horm.Metab.Res. 36:298-302
20. Ito Y, Sørensen KK, Bethea NW, Svistounov D, McCuskey MK, Smedsrød BH, McCuskey RS. (2007). Age-related changes in the hepatic microcirculation in mice. Experimental Gerontology. 48:789-97.
21. Le Couteur DG, Cogger, VC, Hilmer SN, Muller M, Harris M, Sullivan D, McLean AJ, Fraser R. (2006). Aging, Atherosclerosis and the Liver Sieve. In: New Research on Atherosclerosis. Editor: Leon V Clark pp 19-44 Chap 2. Nova Science Publications Inc, New York ISBN 1-59454-942-7.
22. Jamieson HA, Hilmer SN, Cogger VC, Warren A, Cheluvappa R, Abernethy DK, Everitt AV. Fraser R, de Cabo R, Le Couteur DG. (2007). Caloric restriction reduces age-related pseudocapillarisation of hepatic sinusoids. Exp. Ger. 42:374-328.
23. Cogger VC, Hilmer SN, Sullivan D, Muller M, Fraser R, Le Couteur DG.(2006). Hyperlipidemia and surfactants: The liver sieve is a link. Atherosclerosis 189:273-281.
24. Tamba-Lebbie B, Rogers GWT, Dobbs BR, Fraser R (1993). Defenestration of the sinusoidal endothelium of the liver of the dimethylnitrosamine fed rat is a reversible process. In Cells of the Hepatic Sinusoids, Vol. 4. Eds. Wisse E, Knook DL, Leiden, Kupffer Cell Foundation 179-181.

Heart Foundation of Australia Conference
Brisbane 14-16 May 2009

This conference, celebrating the 50th anniversary of the Heart Foundation, included both the importance of lifestyles (especially in women, in which ischaemic heart disease is many times more deadly than breast cancer) and the major risk factors including cholesterol metabolism. From our Tromso work we realised that the porosity of the liver sieve mirrored the risk factors leading to atherosclerotic heart disease. We therefore adjusted our findings and presentation accordingly and submitted an abstract for presentation in the lifestyle section of the conference.

ATHEROSCLEROSIS, LIFESTYLES, LIPOPROTEINS, AND THE LIVER SIEVE

R. Fraser1, B. Dobbs1, H. Jamieson1,2, V. Cogger2, S. Hilmer2, A. Warren2, E. Latimer Hill2, R. Cheluvappa 2, D. Le Couteur2.

1. University of Otago, Christchurch, New Zealand
2. University of Sydney, Concord, NSW, Australia

Introduction

Familial hyperlipoproteinaemias usually follow mutations of genes coding for hepatocyte lipoprotein receptors or apolipoproteins. The more common post-prandial and metabolic dyslipoproteinaemias are related more to lifestyles. The latter often are associated with abnormal ultrastructure of the hepatic microcirculation, especially the gossamer-like fenestrated liver sinusoidal endothelial cells (LSEC), which we termed the liver sieve.

Discussion

The liver sieve with its multiple fenestrae is porous to small lipoproteins, allowing them to contact underlying hepatocyte receptors. Dietary cholesterol, in small chylomicron remnants, thus enters hepatocytes to inhibit endogenous cholesterol synthesis. An increase in the size of chylomicrons and their remnants, as in a high fat diet, or a decrease in porosity of the liver sieve will prevent negative feedback of cholesterol synthesis. Low porosity has been demonstrated in numerous animal and human studies involving nicotine, alcohol, catecholamines, diabetes, endotoxins, sepsis, nitrosamines, surfactants, detergents, cirrhosis, ageing, as well as certain rabbit breeds. Correlations occur between decreased LSEC porosity, hyperlipoproteinaemia and atherosclerosis.

Conclusion

Dyslipoproteinaemia is reversible when LSEC porosity is restored. Lifestyle improvements such as adoption of the Mediterranean diet, increased exercise, low alcohol intake, weight loss and no smoking may improve liver function and decrease hepatic cholesterol synthesis. Even the defenestration of ageing is delayed by caloric restriction.

Powerpoint Presentation Slides

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