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Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-β peptide, and it is associated with increased incidence of cardiovascular and Alzheimer's disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen-deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution. We determined the positions, dynamics, and stabilities of the helical segments in these two proteins, in their normal tetrameric state and in mutation-induced monomeric mutants. Consistent with prior X-ray crystallography and NMR results, the N-terminal domain contains four α-helices, 20 to 30 amino acids long. The C-terminal domain is relatively unstructured in the monomeric state but forms an α-helix ~70 residues long in the self-associated tetrameric state. Helix stabilities are relatively low, 4 kcal/mol to 5 kcal/mol, consistent with flexibility and facile reversible unfolding. Secondary structure in the tetrameric apoE3 and E4 isoforms is similar except that some helical segments in apoE4 spanning residues 12 to 20 and 204 to 210 are unfolded. These conformational differences result from the C112R substitution in the N-terminal helix bundle and likely relate to a reduced ability of apoE4 to form tetramers, thereby increasing the concentration of functional apoE4 monomers, which gives rise to its higher lipid binding compared with apoE3. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the serum levels of Lipoprotein(a) [Lp(a)] in subjects with thyroid disorders, as well as to investigate their relationship with lipid profile and the markers of thyroid function and autoimmunity, admitting that elevated Lp(a) levels and dyslipidemia caused by thyroid disorders synergistically increased the atherogenic process. Methods: This study enrolled 38 subjects with hypothyroidism, 30 with hyperthyroidism and 55 with euthyroidism. The following parameters were measured: Lp(a), apolipoprotein AI (apo AI), apolipoprotein B (apo B), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), very-low-density lipoprotein (VLDL), thyroid stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3), thyroid-peroxidase antibody (TPO-Ab). Results: Lp(a) was found with increased mean serum levels in hypothyroid subjects (483.28 ± 281.55 mg/L). Hyperthyroid subjects showed normal levels (253.13 ± 94.29 mg/L) of Lp(a), but significantly lower than those with hypothyroidism and slightly increased levels in the euthyroid subjects (305 ± 100.44 mg/L). In hypothyroidism a significant positive correlation between Lp(a) and TSH, apo B, TC, TG, TC/HDL, VLDL levels and a negative correlation with FT4, T3 and apo AI/B (p < 0.05) was observed. No correlations were found between serum Lp(a) levels, lipids profile and thyroid function parameters in hyperthyroid subjects, neither with TPO-Ab. Conclusions: The association of hypothyroidism with increased levels of Lp(a) seems to increase the already high cardiovascular risk in the hypothyroid subjects, while increased levels of Lp(a) represents independently a relevant cardiovascular risk factor. [ABSTRACT FROM AUTHOR]

To test the hypothesis that diet may exert differential effects on apolipoprotein (apo) A-I-containing high-density-lipoprotein (HDL) particles with (w) and without (w/o) apo A-II [Lp(A-I w A-II) and Lp(A-I w/o A-II)], the effects of a diet low in saturated fatty acids and cholesterol [National Cholesterol Education Panel (NCEP) Step 2 diet] on these lipoproteins were determined in eight normolipidemic subjects, aged 53-74 y, in both the fasting and nonfasting states. Compared with a diet high in saturated fatty acid and cholesterol, consumption of an NCEP diet (6 mo) lowered fasting plasma, low-density lipoprotein, and HDL cholesterol, and nonfasting plasma cholesterol, triglyceride, and HDL cholesterol (P < 0.05-<0.005). Phospholipid in fasting and nonfasting Lp(A-I w A-II) and Lp(A-I w/o A-II) was lower during the NCEP diet (P < 0.05-0.001), but reductions in apo A-I or A-II were observed only in Lp(A-I w A-II). In contrast, differences in particle-size profiles were detected in Lp(A-I w/o A-II) but not in Lp(A-I w A-II). These observations provide further evidence that Lp(A-I w A-II) and Lp(A-I w/o A-II) are distinct metabolic entities. [ABSTRACT FROM AUTHOR]