Provision of Lipids for Very Low-Density Lipoprotein Assembly

Atherosclerosis is the principal cause of heart attack and stroke in the Western world. The relationship between high levels of low-density lipoprotein (LDL) and atherosclerosis has been known for several decades. LDL is derived from very low-density lipoprotein (VLDL) in the blood via a complex series of reactions involving hydrolases and transfer of lipids and apoproteins among the circulating lipoproteins. Hepatic VLDL assembly and secretion is dependent on lipid availability. Thus stimulation of hepatic triacylglycerol (TG), phospholipid, and cholesterol synthesis increases the secretion of VLDL while inhibition of lipid synthesis has the opposite effect. Several lines of evidence suggest that the assembly of VLDL takes place in two or more steps. The first step involves the generation of dense nascent lipoprotein particles in the endoplasmic reticulum by cotranslational lipidation of apolipoprotein B and these particles mature into a VLDL by posttranslational addition of core lipids such as TG and cholesteryl ester (CE). De novo synthesized TG accounts for only a minor fraction of the TG secreted with VLDL. The majority (60‐70%) of VLDL-TG is derived from lipolysis of stored TG to partial acylglycerols and fatty acids followed by reesterification by the ER-localized acyltransferases. Recently, the genes of a number of enzymes involved in the provision of lipids for VLDL assembly have been cloned and in some cases mice in which these genes were ablated have been obtained. This chapter discusses recent advances in VLDL assembly with emphasis on the lessons learned from genetically modified mouse models.