Triglyceride: one molecule at the center of health and disease.

Fig. 1. Triglyceride transport in the blood. Triglycerides are synthesized in either the intestine or liver. Chylomicrons are secreted into the lymph and then enter the circulation via the superior vena cava. VLDL are directly secreted into the blood. Both particles are metabolized via their interaction with lipoprotein lipase on the luminal surface; a reaction that coverts the triglyceride into free fatty acids that are taken-up by peripheral tissues. Oversupply leads to triglyceride accumulation in heart, skeletal muscle, and liver. In addition, triglyceride-rich lipoproteins can be either a source of atherosclerotic lipids or triglyceride lipolysis might lead to production of lipids that are toxic to the vessels. Why has an entire BBA issue been devoted to triglyceride? During the past several years the BBA has devoted special issues to lipid droplets, lipotoxicity, lipids and Alzheimer's disease, and lipid pathways and human disease. Several of these state of the art reviews have touched on the central molecule of this current issue; triglyceride. The centrality of triglyceride to cellular biology, organ function, and several human diseases is a fast moving scientific and clinical research field and the objective of this issue is to present a birth to death biography of this molecule (Fig. 1). In so doing, I tried to recruit authors who could review issues in triglyceride production, storage, and catabolism, triglyceride and organ dysfunction in animal models, and the correlation of plasma and tissue triglyceride levels with human diseases. This issue is divided into the sections that follow. The first reviews in this issue begin with triglyceride production. Dietary triglyceride is almost 100% absorbed unless there is a defect in pancreatic enzyme production or in enterocyes. Chylomicron triglyceride does not, however, directly enter the bloodstream; rather it is routed via the lymphatics and enters the bloodstream when the thoracic duct empties into the superior vena cava. The reason for this rather circuitous route is uncertain but could be a means to protect the liver from a large lipid load or to allow greater delivery of fatty acids to the heart, lungs and peripheral tissues. Although the process of triglyceride absorption was known to take several hours, recent kinetic analyses reviewed by Drs. Lambert and Parks suggest that enterocyte storage of triglyceride occurs and that the sequence of meals, not just an individual meal, can affect the appearance of dietary chylomicron triglycerides. Major advances in understanding chylomicron assembly have also come from studies of microsomal triglyceride transfer protein (MTTP). Drs. Pan and Hussain discuss what we have learned about the basic pathways of MTTP regulation and how they, in turn, affect gut lipid secretion. Genetic defects in MTTP are the cause of abetalipoproteinemia in humans. However, other factors can lead to a more subtle regulation of triglyceride absorption. Most importantly, Drs. Xiao and Lewis note how insulin can affect chylomicron production, as well as clearance, in humans. The ancients invented the term melancholia, black bile, which occurs with biliary obstruction. Although we longer view the liver as the seat of human passion or emotion, it is clearly the central organ for control of lipid homeostasis. What are the steps regulating the production and secretion of triglyceride from the liver? The primary liver enzyme responsible for de novo hepatic synthesis of triglyceride from glucose is fatty acid synthetase. The biology of this enzyme, much of it learned from genetically modified mice, is reviewed by Drs. Jensen-Urstad and Semenkovich. The liver must allocate its newly formed triglyceride and triglyceride that arrives via lipoprotein and free fatty acid uptake to oxidation, storage or secretion. Phospholipid production, as reviewed by Cole and the Vances, is required both