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

老年是动脉粥样硬化的主要危险因素，动脉粥样硬化继发的血管疾病（如心脏病发作和中风）是西方世界死亡和残疾的主要原因。到目前为止，还没有任何明确的解释，为什么老年本身是动脉粥样硬化的危险因素。在这项研究中，我们正在调查如何在老年肝脏的变化易患胆固醇血症，因此血管疾病。我们最近发现，随着年龄的增长，肝脏血管发生了变化，我们称之为假毛细血管化。这些变化对包括毒素、药物、氧气、激素和脂质在内的许多底物从血液进入肝脏的运输产生了深远的影响，因此可以部分解释老年是许多疾病和药物不良反应的主要风险因素的事实。在这项研究中，我们感兴趣的是转移脂肪称为乳糜微粒残余物从血液进入肝脏。乳糜微粒残留物是富含甘油三酯的脂蛋白，在餐后产生并由肝脏分解。为了被代谢，乳糜微粒残留物必须穿过肝脏血管中的孔，称为开窗。在老年时，我们发现这些开窗显著减少，这将损害肝脏对乳糜微粒残留物的摄取，导致餐后血流中脂肪显著增加。在这项研究中，我们将研究老年对肝脏代谢乳糜微粒残留物的能力的影响，特别是关注与年龄相关的开窗对乳糜微粒残留物摄取的影响。除了提供对衰老和动脉粥样硬化之间关键联系的理解外，这些研究还将为预防老年人动脉粥样硬化提供潜在的新治疗靶点。

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.