The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe

The ApoEurope group, collaborating centres, and their associated investigators: Portugal: Unidade de Química Clínica, Instituto Nacional de Saúde, Lisboa: Maria do Carmo Martins, Maria Odete Rodrigues, Maria Isabel Albergaria, Maria Liseta AlpendreInterindividual variation in the concentration of plasma lipids which are associated with coronary artery disease (CAD) risk is determined by a combination of genetic and environmental factors. This study investigates the effects of apoE genotype and plasma concentration on cholesterol and triglycerides (TG) levels in subjects from five countries: Finland, France, Northern Ireland, Portugal, and Spain. Age and sex significantly influenced serum cholesterol, TG and apoE concentrations. The age effect differs in males and females. The allele frequencies of the apoE gene, one of the most widely studied CAD susceptibility genes, were determined: the epsilon2 allele frequency and the apoE concentration showed a north-south increasing gradient while the epsilon4 allele frequency showed the reverse. ApoE plays an important role in lipid metabolism. Total cholesterol and TG concentrations were significantly dependent on apoE genotype in both sexes. These differences in lipids between genotypes were more pronounced when plasma apoE concentrations were taken into account

A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s

At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4-6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism

Lipids and HCV

Chronic hepatitis C virus (HCV) infection is associated with an increase in hepatic steatosis and a decrease in serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL) and apolipoprotein B (apoB), the main protein constituent of LDL and very low-density lipoprotein (VLDL). These changes are more marked in HCV genotype 3 infection, and effective treatment results in their reversal. Low lipid levels in HCV infection correlate not only with steatosis and more advanced liver fibrosis but also with non-response to interferon-based therapy. The clinical relevance of disrupted lipid metabolism reflects the fact that lipids play a crucial role in the life cycle of hepatitis C virus. HCV assembly and maturation in hepatocytes depend on microsomal triglyceride transfer protein and apoB in a manner that parallels the formation of VLDL. VLDL production from the liver occurs throughout the day with an estimated 1018 particles produced every 24 h whilst the estimated hepatitis C virion production rate is 1012 virions per day. HCV particles in the serum exist as a mixture of complete low-density infectious lipo-viral particles (LVP) and a vast excess of apoB-associated empty nucleocapsid-free sub-viral particles that are complexed with anti-HCV envelope antibodies. Apolipoprotein E (apoE) is also involved in HCV particle morphogenesis and is an essential apolipoprotein for HCV infectivity. ApoE is a critical ligand for the receptor-mediated removal of triglyceride rich lipoprotein (TRL) remnants by the liver. The dynamics of apoB-associated lipoproteins, including HCV-LVP, change post-prandially with an increase in large TRL remnants and very low density HCV-LVP which are rapidly cleared by the liver (at least three HCV receptors are cellular receptors for uptake of TRL remnants). In summary, HCV utilises triglyceride-rich lipoprotein pathways within the liver and the circulation to its advantage