Gregory S. Shelness, PhD
Lipid Biosynthesis; Cellular Lipid Trafficking and Mobilization; Lipoprotein Assembly and Secretion; Targeted Drug Delivery
Apolipoprotein B (apoB) is responsible for the packaging of dietary and endogenous lipids into lipoprotein particles. These particles are distributed to peripheral tissues, such as muscle and adipose, where the lipids are either utilized for energy or stored. However, intravascular metabolism of apoB-containing lipoproteins, particular those originating from liver, give rise to low density lipoproteins (LDL), which in elevated concentrations in the blood cause atherosclerosis and heart disease. Furthermore, imbalances among hepatic and intestinal lipid biosynthesis, storage, utilization and secretion are important in the pathobiology of obesity, type 2 diabetes, and nonalcoholic fatty liver disease.
Our laboratory is studying the process by which apoB, in combination with the microsomal triglyceride transfer protein (MTP) and other cofactors, controls lipid transport by the liver and intestine. Our most recent studies have focused on the unexpected evolutionary origins of lipid transport proteins. It is now clear that MTP is the ancestral member of this gene family and exists in divergent vertebrate and invertebrate species, whose last common ancestor diverged over 550 million years ago. During its long evolutionary history, MTP has acquired distinct functions enabling it to participate in a disparate array of lipid mobilization and transport pathways, ranging from primitive lipoprotein assembly in nematodes and arthropods, to bulk lipid transport and antigenic lipid presentation in humans. Our phylogenic dissection of MTP and apoB function coupled with ongoing structural, biochemical, and biophysical analyses, are providing new insights into mechanisms of lipid mobilization and secretion and strategies to beneficially control disturbances in lipid metabolism associated with chronic disease.
As an outgrowth of our studies on the structure and function of apoB, we are also exploring the use of apoB’s lipid binding domains to achieve the packaging of lipophilic drugs. By fusing apoB to single chain antibodies unique to transformed cells, we hope to achieve the selective delivery of drug-containing complexes to cancer cells without affecting healthy cells and tissues.
Figure Legend: Lipid Mobilization and Secretion by Lipoprotein Producing Cells. Neutral lipids such as triglycerides and cholesterol esters are synthesized by enzymes associated with the endoplasmic reticulum (ER) membrane (1). These lipids are either stored in the cytosol or consumed for energy production (Utilization). Lipid secretion requires the mobilization of cytosolic lipid, a step that involves cytosolic and membrane-associated factors that are not well defined (2). Microsomal triglyceride transfer protein (MTP), which resides in the lumen of the ER, possesses a neutral lipid transfer activity that is required for the generation of lumenal lipid droplets. MTP also functions directly on apolipoprotein B (apoB) to form precursor lipoprotein particles (5). These precursor particles fuse with lipid droplets to form mature intestinal chylomicrons of hepatic VLDL (6), which are then secreted via the classical secretory pathway (7).
Link to PubMed