The Effect of Hepatic Pseudocapillarisation of Old Age on the Disposition of Chylomicron Remnants and Chylomicrons

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Old age is the major risk factor for atherosclerosis, and vascular disease secondary to atherosclerosis (eg heart attacks and strokes) is the major cause of death and disability in the Western World. As yet there has not been any clear explanation for why old age itself is a risk factor for atherosclerosis. In this study, we are investigating how changes in the liver in old age predispose to hyperlipidaemia and hence vascular disease. We recently discovered changes in the blood vessels of the liver that occur with old age that we have called pseudocapillarisation. These changes have profound effects on the transport of many substrates including toxins, drugs, oxygen, hormones and lipids from the blood into the liver and thus may explain in part the fact that old age is the major risk factor for many diseases and adverse drug reactions. In this study we are interested in the transfer of fats called chylomicron remnants from blood into the liver. Chylomicron remnants are lipoproteins rich in triglycerides that are produced after meals and broken down by the liver. In order to be metabolised, chylomicron remnants must pass through pores in the liver blood vessels called fenestrations. In old age, we have found that these fenestrations are reduced substantially, which will impair the uptake of chylomicron remnants by the liver, leading to marked increases in fat in the blood stream after meals. In this study, we will examine the effects of old age on the ability of the liver to metabolise chylomicron remnants, in particular focussing on the effects of the age-related loss of fenestrations on chylomicron remnant uptake. As well as providing an understanding of the crucial link between ageing and atherosclerosis, the studies will provide a potential new therapeutic target for the prevention of atherosclerosis in older people.