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 (LDL), 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 (ER), they are transported to the Golgi. The transport of nascent VLDLs from the ER to Golgi is a complex multi-step process, which is mediated by a specialized transport vesicle, the VLDL transport vesicle (VTV). The VTV 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.

Recent advances in physiological lipoprotein metabolism

“…The production of VLDLs needs to be synchronized with their secretion to avoid adverse consequences such as hepatic steatosis and higher concentrations of VLDLs in the blood. There are three main sources that supply free fatty acids to the liver: 1) free fatty acids from adipocytes; 2) chylomicron remnants; and 3) the intestine via the portal vein [97]. Mobilized lipid storage pool in the liver, de novo synthesis of fatty acids and phospholipids contribute to hepatic VLDL synthesis.…”

mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion

“…The stimulation of VLDL-TAG export from the liver facilitates systemic lipid transport to extrahepatic tissues. Importantly, VLDL-TAG secretion is central to the regulation of hepatic and circulating lipid levels; thus, increases in VLDL-TAG contribute to hyperlipidemia and metabolic disease (4,5).…”

“…These data identify mTORC1 as a major regulator of phospholipid biosynthesis and subsequent VLDL-TAG secretion, leading to increased postprandial TAG secretion. mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion 4 mTORC1 (L-TSC-KO) led to significantly reduced liver TAG during both fasting and the prandial state ( Figure 1D). In addition, L-Raptor-KO mice exhibited an increase in total hepatic TAG despite a reduction in liver size, while L-TSC-KO mice had significantly reduced TAG in liver ( Figure 1E).…”

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

“…A major type of lipoprotein, the very low density lipoprotein (VLDL), is synthesized and assembled in hepatocytes and secreted into the plasma to be delivered to other organs through the circulation [5,6]. VLDL assembly and secretion from the liver plays an important role in controlling plasma levels of triglycerides (TGs) and cholesterol, and many proteins and lipids are known to be involved in this process [7].…”