Epidemiological characterisation of afamin

Previous work from our group has identified the human plasma protein afamin as a novel vitamin E-binding protein. Afamin belongs to the albumin gene familiy, is expressed in liver and kidney and secreted into the plasma. Afamin might have important functions in fertility and neuroprotection since it has been abundantly found in extravascular fluids such as follicular, seminal and cerebrospinal fluids and exerts neuroprotective properties in vitro. First preliminary results from chimeric afamin-gene-deletion mice seem to confirm these assumptions. Very recently, we generated several lines of transgenic mice overexpressing the human afamin gene and observed changes in lipid metabolism and body weight directing a possible physiologic or pathophysiologic function of afamin in a totally different direction. Plasma concentrations of most lipids and lipoproteins (total and LDL- cholesterol, triglycerides) as well as the mean body weight of transgenic animals were significantly elevated as compared with age-matched wild-type littermates. These preliminary findings of a hyperlipemic/-glycemic and obese phenotype suggest a (possibly causal) role of afamin in epidemic diseases such as diabetes, metabolic syndrome and cardiovascular disease. Based on these previous findings, we propose to investigate the above-mentioned putative pathophysiologic role of afamin by the following 2 major approaches: a) continue and extend the detailed metabolic characterization of the afamin transgenic mice with focusing on parameters of lipid, lipoprotein and glucose metabolism. b) Measure plasma afamin concentrations in three already existing study populations with different study designs and investigate the association of afamin with genotypes, intermediate phenotypes and clinical endpoints related to cardiovascular disease, obesity and metabolic syndrome. If a functional role of afamin in lipid/lipoprotein and glucose metabolism (as suggested by our preliminary data from the transgenic mouse model) can be established in large human populations, afamin could present an exiting novel key target for therapeutic intervention to combat the modern epidemic metabolic syndrome.

Previous work from our group has identified the human plasma protein afamin as a novel vitamin E-binding protein. Afamin belongs to the albumin gene familiy, is expressed in liver and kidney and secreted into the plasma. Afamin might have important functions in fertility and neuroprotection since it has been abundantly found in extravascular fluids such as follicular, seminal and cerebrospinal fluids and exerts neuroprotective properties in vitro. First preliminary results from chimeric afamin-gene-deletion mice seem to confirm these assumptions. Very recently, we generated several lines of transgenic mice overexpressing the human afamin gene and observed changes in lipid metabolism and body weight directing a possible physiologic or pathophysiologic function of afamin in a totally different direction. Plasma concentrations of most lipids and lipoproteins (total and LDL- cholesterol, triglycerides) as well as the mean body weight of transgenic animals were significantly elevated as compared with age-matched wild-type littermates. These preliminary findings of a hyperlipemic/-glycemic and obese phenotype suggest a (possibly causal) role of afamin in epidemic diseases such as diabetes, metabolic syndrome and cardiovascular disease. Based on these previous findings, we propose to investigate the above-mentioned putative pathophysiologic role of afamin by the following 2 major approaches: 1. continue and extend the detailed metabolic characterization of the afamin transgenic mice with focusing on parameters of lipid, lipoprotein and glucose metabolism. 2. Measure plasma afamin concentrations in three already existing study populations with different study designs and investigate the association of afamin with genotypes, intermediate phenotypes and clinical endpoints related to cardiovascular disease, obesity and metabolic syndrome. If a functional role of afamin in lipid/lipoprotein and glucose metabolism (as suggested by our preliminary data from the transgenic mouse model) can be established in large human populations, afamin could present an exiting novel key target for therapeutic intervention to combat the modern epidemic metabolic syndrome.