Intracellular trafficking and secretion of VLDL

Abstract

Steady increase in the incidence of atherosclerosis is becoming a major concern not only in the United States but also in other countries. One of the major risk factors for the development of atherosclerosis is high concentrations of plasma low-density lipoprotein, which are metabolic products of very low-density lipoprotein (VLDL). VLDLs are synthesized and secreted by the liver. In this review, we discuss various stages through which VLDL particles go from their biogenesis to secretion in the circulatory system. Once VLDLs are synthesized in the lumen of the endoplasmic reticulum, they are transported to the Golgi. The transport of nascent VLDLs from the endoplasmic reticulum to Golgi is a complex multistep process, which is mediated by a specialized transport vesicle, the VLDL transport vesicle. The VLDL transport vesicle delivers VLDLs to the cis-Golgi lumen where nascent VLDLs undergo a number of essential modifications. The mature VLDL particles are then transported to the plasma membrane and secreted in the circulatory system. Understanding of molecular mechanisms and identification of factors regulating the complex intracellular VLDL trafficking will provide insight into the pathophysiology of various metabolic disorders associated with abnormal VLDL secretion and identify potential new therapeutic targets.

Figure 1

VLDL transport from the ER to the Golgi in hepatocytes. The assembly of VLDLs occurs in the lumen of the endoplasmic reticulum (ER). After their biogenesis in the ER lumen, VLDLs are packaged into specialized vesicles known as VLDL transport vesicles (VTVs). The average diameter of the VTVs is ~110 nm, which is sufficient to enclose VLDL-sized particles. VTVs bud off the ER membrane and move to and fuse with the cis-Golgi, delivering their VLDL cargo to the Golgi lumen. Proteins involved in VLDL-selection into VTV and VTV-Golgi docking are not known yet. Nascent proteins are transported from the ER to the Golgi protein transport vesicles (PTVs). Their size ranges between ~55 and 70 nm. Although biogenesis of both VTVs and PTVs from the ER membrane requires coat protein complex II (COPII) machinery, different homologs of Sar1 are required for their budding process (shown in bold). VTVs are, however, different from PTVs in their size, buoyant density, cargo, protein composition and require a unique set of SNARE proteins for fusion-complex formation.