Lipid and Lipoprotein Metabolism

Abstract

Lipoprotein metabolism can be subdivided into transport of exogenous lipids, transport of endogenous lipids from the liver to peripheral tissues, and reverse cholesterol transport with eventual excretion of cholesterol and its catabolic end products, bile salts, into the bile. Lipids are transported through the bloodstream as macromolecular complexes called lipoproteins, of which there are a number of classes that can be separated by sequential ultracentrifugation. Lipoprotein particles consist of a hydrophobic lipid core that is stabilized by a monolayer of phospholipids, free cholesterol, and apolipoproteins. Nine apolipoproteins are members of a multigene family. Eight of these are clustered at two loci: apoA-I, apoA-IV, apoA-V, and apoC-III on chromosome 11; and apoC-I, apoC-II apoC-IV, and apoE on chromosome 19. The apoB gene codes for two major structural proteins, one of which is produced by a novel mRNA editing mechanism. There are an increasing number of key genes recognized that play important roles in lipid metabolism and transport. Those that code for intracellular proteins involved in cholesterol synthesis, storage, or catabolism include HMGCoA synthase (HMGCS1), HMGCoA reductase (HMGCR), acyl-CoA:cholesterol acyltransferase (ACAT1/SOAT1 and ACAT2/SOAT2), and cholesterol 7α-hydroxylase (CYP7A1). The diacylglycerol O-acyltransferases (DGAT1 and DGAT2) are important in triglyceride synthesis. The microsomal triglyceride transfer protein (MTP) is a major participant in the assembly of very low density lipoproteins (VLDL). There is a family of lipoprotein receptor genes, most notable of which is the LDL receptor. Similarly, there is a family of lipases including lipoprotein lipase (LPL), hepatic triglyceride lipase (LIPC), and endothelial lipase (LIPG). In addition to the apolipoproteins, but also associated with lipoproteins, are a number of gene products that are important for lipid transport. These include lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), and cholesterol ester transfer protein (CETP). Key genes involved in reverse cholesterol transport are ATP-binding cassette A1 (ABCA1), scavenger receptor SR-BI/CLA1 (SCARB1), and caveolin (CAV1). Other members of the ABC transporter family are being increasingly seen as major players in lipid transport. For example, ABCA7 and ABCB4 are phospholipid transporters, and ABCB11 is the bile salt export protein. Over the last decade, a number of nuclear receptors that regulate the genes mentioned above have been identified. These include the sterol regulatory element binding proteins (SREBPs), the liver X receptors (LXRα, NR1H3, and LXRβ, NR1H2), the farnesoid X receptor (FXR, NR1H4), and the peroxisome proliferator-activated receptors (PPARα, PPARγ, and PPARδ). Recent advances in molecular cell biology and molecular medicine, involving studies of these genes and their products, have significantly increased our understanding of lipoprotein metabolism and atherosclerotic heart disease.