- University of Otago, Christchurch, New Zealand
R. Fraser, B. Dobbs, H. Jamieson
- University of Sydney, Concord, NSW, Australia
V. Cogger, S. Hilmer, A. Warren, E. Latimer Hill, R. Cheluvappa, D. Le Couteur
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.
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.
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.
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