The high affinity of human plasma β2-glycoprotein I (β 2 GPI), also known as apolipoprotein-H (ApoH), for negatively charged phospholipids determines its implication in a variety of physiological pathways, including blood coagulation and the immune response. β 2 GPI is considered to be a cofactor for the binding of serum autoantibodies from antiphospholipid syndrome (APS) and correlated with thrombosis, lupus erythematosus and recurrent fetal loss. We solved the β 2 GPI structure from a crystal form with 84% solvent and present a model containing all 326 amino acid residues and four glycans. The structure reveals four complement control protein modules and a distinctly folding fifth C-terminal domain arranged like beads on a string to form an elongated J-shaped molecule. Domain V folds into a central β-spiral of four antiparallel β-sheets with two small helices and an extended C-terminal loop region. It carries a distinct positive charge and the sequence motif CKNKEKKC close to the hydrophobic loop composed of residues LAFW (313-316), resulting in an excellent counterpart for interactions with negatively charged amphiphilic substances. The β 2 GPI structure reveals potential autoantibody-binding sites and supports mutagenesis studies where Trp316 and CKNKEKKC have been found to be essential for the phospholipid-binding capacity of β 2 GPI.

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In a comprehensive study the concentrations of plasma lipids and lipo- and apolipoproteins were measured in 24 nonpregnant women (control) and longitudinally in 42 women throughout gestation and postpartum. The results were correlated with hCG, 17 beta-estradiol (E2), progesterone (PG), human placental lactogen (hPL), and insulin levels by time series analysis. Insulin concentrations were constant until week 25 and increased thereafter. Plasma E2, PG, and hPL as well as plasma lipid levels rose continuously during gestation. Apolipoproteins AI, AII, and B concentrations increased until weeks 25, 28, and 32, respectively, and remained constant until term. Low density lipoprotein cholesterol reached maximum levels at week 36. High density lipoprotein cholesterol exhibited a triphasic behavior, with maximum levels at week 25, a fall until week 32, and maintenance of the level until term. Time series analysis revealed positive correlations with E2, PG, and hPL. These results provide evidence that apoprotein concentrations undergo pronounced serial changes during gestation, which in part might be due to the effect of E2. Furthermore, the importance of hPL as a determinant of the plasma levels of total and free cholesterol, triglycerides, and phospholipids is now documented.

A B S T R A C T An elevated concentration of lipoprotein (a) [Lp(a)] in the serum has been considered a risk factor for coronary heart disease by various investigators. In the present study, the turnover of Lp(a) was investigated in nine individuals with serum Lp(a) levels ranging from 1 to 68 mg/100 ml. After intravenous injection of radioiodinated Lp(a), the radioactivity time-curve of the serum and the specific activitity time-curves of the isolated Lp(a) and Lp(a) apolipoproteins were measured for 14 d. More than 97% of the label was found in the protein moiety of Lp(a). During the entire study period, the serum radioactivity remained with Lp(a), only insignificant amounts of radioactivity were detectable in other lipoprotein fractions. The serum radioactivity timecurves and the specific activity time-curves of the isolated Lp(a) and Lp(a) apolipoproteins were identical.The kinetic parameters of Lp(a) turnover were calculated in terms of a two-compartment model.

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Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism. LXR agonists have been shown to limit the cellular cholesterol content by inducing reverse cholesterol transport, increasing bile acid production, and inhibiting intestinal cholesterol absorption. Most of them, however, also increase lipogenesis via sterol regulatory element-binding protein-1c (SREBP1c) and carbohydrate response element-binding protein activation resulting in hypertriglyceridemia and liver steatosis. We report on the antiatherogenic properties of the steroidal liver X receptor agonist N,N-dimethyl-3b-hydroxy-cholenamide (DMHCA) in apolipoprotein E (apoE)-deficient mice. Long-term administration of DMHCA (11 weeks) significantly reduced lesion formation in male and female apoE-null mice. Notably, DMHCA neither increased hepatic triglyceride (TG) levels in male nor female apoE-deficient mice. ATP binding cassette transporter A1 and G1 and cholesterol 7a-hydroxylase mRNA abundances were increased, whereas SREBP1c mRNA expression was unchanged in liver, and even decreased in macrophages and intestine. Short-term treatment revealed even higher changes on mRNA regulation. Our data provide evidence that DMHCA is a strong candidate as therapeutic agent for the treatment or prevention of atherosclerosis, circumventing the negative side effects of other LXR agonists. Nuclear liver X receptors (LXRs) are involved in the control of cholesterol and lipid metabolism. LXRa (NR1H3) and LXRb (NR1H2) are sterol sensors that bind oxysterols to act as a transcriptional switch for the coordinated regulation of genes involved in cellular cholesterol homeostasis, cholesterol transport, catabolism, and absorption (1). In peripheral cells such as macrophages, LXRs are likely to coordinate a physiological response to cholesterol loading by regulating the transcription of several genes involved in cholesterol efflux and catabolism, including ATP-binding cassette (ABC)A1 and G1 (2-6).

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