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.
