AGING IN A HYPERLIPIDEMIC ENVIRONMENT

高脂血症在老年人中流行，是心脏病的既定危险因素。随着人口老龄化，肝病的发展往往伴随着高脂血症。高脂血症和肝损伤之间的因果关系尚未得到研究。此外，关于慢性高脂血症对衰老肝脏的影响的基本信息也是缺乏的。R03号试验性提案的主要重点是与正常血脂小鼠相比，基本了解热量限制对高脂血症小鼠的年龄相关肝功能变化的影响。这一建议建立在我们实验室的最新发现基础上，这些发现表明，与正常小鼠或无关的对照组小鼠相比，高脂血症雄性和雌性小鼠在8-10个月龄时会患上肝纤维化前期疾病。这项研究将使用年龄和性别匹配的正常和转基因小鼠，这些小鼠过度表达载脂蛋白C-I，出现混合性高脂血症。正常和高脂血症转基因小鼠在5个月、10个月和15个月后自由进食食物或长期限制能量摄入(基于自由进食减少40%)将被调查，以确定血浆脂质和脂蛋白水平的变化。活体显微镜将被用来确定肝脏微血管的变化；每组的肝脏代谢指标将被监测，以评估整体功能。该项目将提供有关正常血脂和高脂血症状态下与年龄相关的肝脏变化的基本新信息。了解肝脏中年龄相关的衰减可能有助于阐明与年龄相关的系统功能变化、疾病发展、药物代谢和对急性应激的敏感性的机制。

Hyperlipidemia, pandemic among aging individuals, is an established risk factor for heart disease. The development of liver disease in the aging human population is frequently accompanied by hyperlipidemia. A causal relationship between hyperlipidemia and liver damage has not been investigated. Furthermore, basic information concerning the effect of chronic hyperlipidemia on the aging liver is lacking. This pilot R03 proposal has as its primary focus to achieve a basic understanding of the influence of caloric restriction on the age related changes in liver function observed in hyperlipidemic mice as compared with normolipidemic littermates. This proposal builds on recent findings in our laboratory that show hyperlipidemic male and female mice develop prefibrotic liver disease by 8 - 10 months of age as compared with normal littermates or unrelated control mice. This study will use age and sex-matched normal and transgenic mice overexpressing apolipoprotein C-I that present with combined hyperlipidemia. Normal and hyperlipidemic transgenic mice at 5, 10 and 15 months maintained on ad libitum access to chow or on chronic energy intake restriction (40% reduction based on ad libitum consumption) will be investigated to determine changes in plasma lipids and lipoprotein levels. Intravital microscopy will be used to determine liver microvascular changes; and liver metabolic indicators will be monitored in each group to evaluate overall function. This project will provide fundamental, new information regarding age-related changes in the liver under normolipidemic and hyperlipidemic states. Understanding age-dependent attenuation in the liver has the potential to contribute to elucidating mechanisms in age-related alterations in systemic function, disease development, drug metabolism and susceptibility to acute stresses.