Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8.

Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty years since its discovery. The genomic era has revealed that there are far more carriers of loss of function mutations and likely pathogenic variants of ABCG5 ABCG8 than previously thought. The impact of these variants on G5G8 structure and activity are largely unknown. We propose a classification system for ABCG5 ABCG8 mutants based on previously published systems for diseases caused by defects in ABC transporters. This system establishes a framework for the comprehensive analysis of disease-associated variants and their impact on G5G8 structure-function.

Tissue factor pathway inhibitor: then and now.

Tissue factor pathway inhibitor (TFPI) is the major physiological regulator of tissue factor (TF)-induced blood coagulation. TFPI inhibits the TF-activated factor VII (FVIIa) complex in an activated factor X (FXa)-dependent manner, helping to control thrombin generation and ultimately fibrin formation. The importance of TFPI is demonstrated in models of hemophilia where lower levels of FVIII or FIX are insufficient to overcome its inhibitory effect, resulting in a bleeding phenotype. There are two major isoforms in vivo; TFPIα contains three Kunitz-type inhibitory domains (designated K1, K2, and K3), is secreted by endothelial cells and requires protein S to enhance its anticoagulant activity. In contrast, TFPIß contains only the K1 and K2 domains, but it is attached to the endothelial surface via a glycosylphosphatidylinositol anchor. This review will initially provide a brief history of the major discoveries related to TFPI, and then discuss new insights into the physiology of TFPI, including updates on its association with protein S and FV, as well as the current understanding of its association with disease.

Triglyceride-rich lipoproteins and plasma lipid transport.

This memoir provides a history of the triglyceride-rich lipoproteins of blood plasma over the last half-century. As precursors of low-density lipoproteins and in their own right, triglyceride-rich lipoproteins are essential to the formation of atherosclerotic plaques and to consequent ischemic vascular disease. The author recounts research at the National Heart Institute during 1953 to 1956 and continuing thereafter at the University of California San Francisco. Emphasis is placed on key insights arising from investigations of human disease, the interplay of fatty acid and triglyceride-transport involving the liver, small intestine, adipose tissue and muscle, and the role of the liver in the synthesis and catabolism of atherogenic lipoproteins.

History of lipidology and lipoprotein apheresis.

This review tells the story of atherosclerosis research in the beginning of the 20th century. It presents the significance of cardiovascular diseases and addresses major questions currently being discussed among lipidologists and the current thinking with respect to low LDL-cholesterol levels and HDL. It provides an overview of the period during which lipid-modifying drugs were introduced and their relevance with respect to cardiovascular outcome data and lists possible reasons why some patients develop new cardiovascular events while being treated with statins. Especially impressive is the history of the appearance of the PCSK9 inhibitors on the market - only 12 years after PCSK9 was detected; a study completed in 2017 provides evidence about the cardiovascular effects of these new drugs. Other new drugs are also mentioned: mipomersen, lomitapide, and Alipogen Tiparvovec. Some promising drugs are still in the pipeline which inhibit the synthesis of apolipoprotein CIII, apolipoprotein(a), and the PCSK9 protein. During the 1970s, specific lipoprotein apheresis began to be used in high-risk patients with homozygous familial hypercholesterolemia, severe hypercholesterolemia and elevated Lipoprotein(a) levels and this review provides evidence of the effectiveness of the extracorporeal therapy with respect to the reduction of cardiovascular events. Particularly in patients with high Lipoprotein(a) levels, apheresis has been proven capable of reducing cardiovascular events by more than 80%. The current situation with regard to lipoprotein apheresis centers and patients in Germany is described herein, and, in conclusion, an estimation of the future of the therapeutic options in lipidology is given.

A brief history of lipid and lipoprotein measurements and their contribution to clinical chemistry.

The study of modern lipid chemistry began in the 17th and 18th centuries with early observations by Robert Boyle, Poulletier de la Salle, Antoine François de Fourcroy and others. The 19th century chemist, Chevreul, identified several fatty acids, suggested the name 'cholesterine' for the fatty substance in gallstones, coined the word 'glycerine', and showed that fats were comprised of glycerol and fatty acids. The 20th century brought many advances in the understanding of lipoprotein structure and function, and explored relationships between lipoproteins and disease states. The development of the ultracentrifuge and other lipoprotein separation techniques, and reagents for accurate, standardized quantitative measurement have steadily increased our understanding of the important role of lipoprotein metabolism in both healthy and disease states.

Lipoprotein analysis. Early methods in the diagnosis of atherosclerosis.

Before 1950, there was no clear perception of the interrelationship of serum lipids, atherosclerosis, and coronary heart disease. Since then, research laboratories have made conflicting claims for the most useful measurement of the serum lipid levels in detecting and managing coronary heart disease. Emphasis has been placed in turn on the measurement of levels of serum cholesterol, lipoproteins, triglycerides, and, currently, cholesterol and lipoproteins again. Physical separation and characterization of serum lipoproteins by ultracentrifugation and electrophoresis resulted in two classification systems for lipoproteins based on hydrated density and electrophoretic mobility, respectively. Two operational by-products were the atherogenic index, an empirical formula supposed to correlate with coronary heart disease, and a phenotype system for classification of the lipoproteinemias. Current National Heart, Lung, and Blood Institute criteria for atherosclerosis risk implicate elevated levels of cholesterol and low-density lipoprotein cholesterol, and decreased levels of high-density lipoprotein cholesterol. Although triglycerides are closely associated with cholesterol in lipoprotein molecules and are positively associated with cardiovascular disease, there is no strong evidence of elevated levels of plasma triglycerides as an independent risk factor in coronary heart disease. Elevated levels of triglycerides can help identify persons with increased risk of cardiovascular disease from other causes, but screening for hypertriglyceridemia is not recommended. Apolipoproteins and lipoprotein Lp(a) are briefly discussed.

[Contribution of Jacques Canal in the field of lipoproteins]. / Contribution apportée par Jacques Canal dans le domaine des lipoprotéines.

The scientific works of J. Canal have essentially related to low density lipoproteins (L.D.L.), between 1.025 and 1.050. By using proteolytic enzymes and phospholipases, he is able to obtain informations on the accessibility of apolipoprotein B and phospholipids. So, as early as 1975, he expresses the hypothesis that only 30 p. cent of Apo B occupy a superficial position. In addition, he proposes the fact that Apo B has at least four antigenic determinants; this hypothesis formulated by J. Canal, almost 10 years ago, was recently confirmed by using monoclonal antibodies. At the same time, using phospholipases, J. Canal reaches the conclusion that phospholipids are localized on the surface of L.D.L. He demonstrates that phospholipids play a major role in the precipitation of L.D.L. by sulfate polysaccharides in the presence of L.D.L. by sulfated polysaccharides in the presence of divalent cations (Reaction of Burnstein). He proposes a mechanism for this reaction. This research on the mechanism of Burnstein's reaction will receive in clinical biochemistry an important application with the development of a completely original technique of dosage of total lipids in the serum.

Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I.

This is the first of a series of reviews of the controversy that swirled around the "lipid hypothesis" of atherosclerosis for so many years. Today, in the era of the statins, there is no longer any doubt about the value of decreasing blood cholesterol levels. In fact, "the lower the better" is the position of many clinicians. However, getting to this point has been a long uphill battle marked by heated debate and sometimes violent disagreement. The history of this controversy is worth telling for its own sake and because remembering it may help us avoid similar mistakes in the future. The history of this controversy is worth telling for its own sake and because remembering it may help us avoid similar mistakes in the future.

Preventing coronary artery disease by lowering cholesterol levels: fifty years from bench to bedside.

In the more than 50 years since the founding of the National Heart, Lung, and Blood Institute and the American Heart Association, medical science has moved from an era in which hypercholesterolemia, as it is now defined, was not believed to be abnormal to one in which controlling hypercholesterolemia is known to reduce not only coronary artery disease morbidity and mortality but also total mortality. While the efforts and successes of many researchers involved in this evolution are impressive, atherosclerosis is still a major cause of death and disability in many developed nations, mostly in the form of myocardial infarction and stroke, and is an increasing cause of morbidity and mortality in developing nations. Many questions about the detailed pathogenesis of the disease remain. Elucidating the roles of high-density lipoprotein, other lipoproteins, and homocysteine, as well as the roles of cytokines and growth factors, will permit better understanding and treatment of atherosclerosis. With continuing support for research and encouragement of physicians and patients to follow recommended preventive regimens, further progress can be made against this major cause of death.

Las grasas y aceites en la nutrición humana: algo de su historia / Fats and oils in the human nutrition: an historical overview

Las grasas y aceites, también identificadas como materias grasas, constituyen la forma mayoritariamente comestible de los lípidos. Actualmente muestran un gran desarrollo tecnológico y nutricional, aunque su utilización en la alimentación y en usos domésticos comenzó hace muchos siglos. La Revolución Industrial significó un salto cuantitativo en el conocimiento de las materias grasas. El francés Eugene Chevreul fue el iniciador de la investigación científica en grasas y aceites. Jean-Baptiste Dumas en Francia y Justus Liebig, en Alemania, dieron origen a los primeros conceptos sobre la importancia nutricional de las grasas y aceites. Hypolitte Mége-Mouriés desarrollo un procedimiento para obtener un producto similar a las actuales margarinas. El alemán Franz Knoop fue el descubridor del proceso bioquímico de metabolización de los ácidos grasos conocido como beta oxidación. Los norteamericanos George y Mildred Burr descubrieron la esencialidad de los ácidos grasos, y las investigaciones de los ingleses Haslan y Chick, en forma independiente, caracterizaron las primeras lipoproteínas. Este trabajo resume en forma no exhaustiva los primeros descubrimientos relacionados con el rol nutricional de las grasas y de los aceites.

Fats and oils, also identified as fats, are the main components of edible lipids. The technological and the nutritional knowledge of fats and oils is at present very well developed, however the utilization of fats as foods or for domestic uses was initiated many centuries ago. The named Industrial Revolution represented a significant quantitative development in the knowledge of fats and oils. The French Eugene Chevreul was probably the first scientific who studied the properties of fats and oils. Another French citizen, Jean-Baptiste Dumas together with the German scientist Justus Liebig, were the first researchers who intended to explain the nutritional properties of fats. The French pharmacist Hypolitte Mége-Mouriés was involved in the preparation of the first fat emulsion which resembles a margarine. The German scientist Franz Knoop described the biochemical process known as beta oxidation of fatty acids. George and Mildred Burr, both American scientists, were the first to describe the essentiality of fatty acids, and the English Haslan and Chick independently isolated the first lipoproteins. The present description review, although not exhaustively, the main discoveries about the nutritional role of fats and oils.