Lipoprotein modification

Abstract: Covalent modification of membrane proteins with lipids appears to be ubiquitous in all living cells. The major outer membrane (Braun's) lipoprotein of E. coli, the prototype of bacterial lipoproteins, is first synthesized as a precursor protein. Analysis of signal sequences of 26 distinct lipoprotein precursors has revealed a consensus sequence of lipoprotein modification/processing site of Leu-(Ala, Ser)-(Gly, Ala)-Cys at -3 to +1 positions which would represent the cleavage region of about three-fourth of all lipoprotein signal sequences in bacteria. Unmodified prolipoprotein with the putative consensus sequence undergoes sequential modification and processing reactions catalyzed by glyceryl transferase, O-acyl transferase(s), prolipoprotein signal peptidase (signal peptidase II), and N-acyl transferase to form mature lipoprotein. Like all exported proteins, the export of lipoprotein requires functional SecA, SecY, and SecD proteins. Thus all precursor proteins are exported through a common pathway accessible to both signal peptidase I and signal peptidase II. The rapidly increasing list of lipid-modified proteins in both prokaryotic as well as eukaryotic cells indicates that lipoproteins comprise a diverse group of structurally and functionally distinct proteins. They share a common structural feature which is derived from a common biosynthetic pathway.

Abstract: Cellular processes in atherogenesis with the exception of calcification and thrombotic events are principally no different to those found in chronic inflammatoryfibroproliferative diseases such as liver cirrhosis, rheumatoid arthritis, glomerulosclerosis, pulmonary fibrosis, or chronic pancreatitis [1]. Atherosclerotic lesions are the result of a series of highly specific cellular and molecular responses to various endogenous risk factors and potential exogenous antigens. These responses are mediated by endothelial cells, monocyte-derived macrophages, smooth muscle cells and specific subtypes of T lymphocytes. Activation of these cells leads to the release of a wide spectrum of inflammatory hydrolases, cytokines, chemokines and growth factors followed by cellular lipid accumulation and proliferation of smooth muscle cells as well as formation of fibrous tissue [2]. The modified response-to-injury hypothesis of atherosclerosis that emphasizes endothelial dysfunction rather than denudation as the first step in atherosclerosis [1] was recently extended suggesting that the key initiating event in early atherosclerosis is the subendothelial retention of cholesterol-rich, atherogenic lipoproteins bound to arterial proteoglycans (response-to-retention hypothesis) [3]. Following adherence to endothelial cells, defined subpopulations of circulating monocytes that express the lipopolysaccharide (LPS) receptor CD14 and the FcyRIII/CD16 (CD14bright CD16) might extravasate into the subendothelial space [4-6]. Within the vessel wall phagocytic monocytes rapidly transform to foam cells characterized by the excessive uptake of atherogenic lipoproteins by receptor-mediated endocytosis. Cellular uptake of these lipids and lipoproteins is mediated by charge and motif receptors (scavenger receptors) directly recognizing non-opsonized ligands. Alternatively, modified lipids and lipoproteins may be opsonized by either innate (complement components, C-reactive protein (CRP), serum amyloid P (SAP), serum amyloid A (SAA)) and/or specific opsonins (immunoglobulins) prior to cellular uptake mediated by different opsonin receptors including complement receptors, pentraxin family receptors and/or Fcy-receptors. Continuous exposure to modified lipoproteins is supposed to trigger a chronic identification of the opsonins and opsonin receptors relevant for cellular uptake and signalling represent important goals in cardiovascular disease research, in particular with respect to the development of therapeutic strategies to prevent or reverse lipoprotein modification or opsonization.

Abstract: We investigated lipid profiles and lipoprotein modification after immuno-intervention in patients with early rheumatoid arthritis (ERA). Fifty-eight patients with ERA who met the American College of Rheumatology (ACR) criteria were included in the study. These patients had disease durations of less than one year and had not had prior treatment for it. Smokers or patients suffering from diabetes mellitus, hypothyroidism, liver or kidney disease, Cushing's syndrome, obesity, familiar dyslipidemia and those receiving medications affecting lipid metabolism were excluded from the study. Sixty-three healthy volunteers (controls) were also included. Patients were treated with methotrexate and prednisone. Lipid profiles, disease activity for the 28 joint indices score (DAS-28) as well as ACR 50% response criteria were determined for all patients. The mean DAS-28 at disease onset was 5.8 ± 0.9. After a year of therapy, 53 (91.3%) patients achieved the ACR 20% response criteria, while 45 (77.6%) attained the ACR 50% criteria. In addition, a significant decrease in the DAS-28, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were observed. ERA patients exhibited higher serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides, whereas their serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower compared to controls. As a consequence, the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was significantly higher in ERA patients compared to controls. After treatment, a significant reduction of the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was observed, a phenomenon primarily due to the increase of serum HDL-C levels. These changes were inversely correlated with laboratory changes, especially CRP and ESR. In conclusion, ERA patients are characterized by an atherogenic lipid profile, which improves after therapy. Thus, early immuno-intervention to control disease activity may reduce the risk of the atherosclerotic process and cardiovascular events in ERA patients.

Abstract: Recent years have brought a significant amount of new results in the field of atherosclerosis. A better understanding of the role of different lipoprotein particles in the formation of atherosclerotic plaques is now possible. Recent cardiovascular clinical trials have also shed more light upon the efficacy and safety of novel compounds targeting the main pathways of atherosclerosis and its cardiovascular complications. In this review, we first provide a background consisting of the current understanding of the pathophysiology and treatment of atherosclerotic disease, followed by our future perspectives on several novel classes of drugs that target atherosclerosis. The focus of this update is on the pathophysiology and medical interventions of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and lipoprotein(a) (Lp(a)).