Very-low-density lipoprotein assembly and secretion

Abstract

The assembly of apolipoprotein B (apoB) into VLDL is broadly divided into two steps. The first involves transfer of lipid by the microsomal triglyceride transfer protein (MTP) to apoB during translation. The second involves fusion of apoB-containing precursor particles with triglyceride droplets to form mature VLDL. ApoB and MTP are homologs of the egg yolk storage protein, lipovitellin. Homodimerization surfaces in lipovitellin are reutilized in apoB and MTP to achieve apoB-MTP interactions necessary for first step assembly. Structural modeling predicts a small lipovitellin-like lipid binding cavity in MTP and a transient lipovitellin-like cavity in apoB important for nucleation of lipid sequestration. The formation of triglyceride droplets in the endoplasmic reticulum requires MTP however, their fusion with apoB may be MTP-independent. Second step assembly is modulated by phospholipase D and A2. Phospholipases may prime membrane transport steps required for second step fusion and/or channel phospholipids into a pathway for VLDL triglyceride production. The enzymology of VLDL triglyceride synthesis is still poorly understood; however, it appears that ACAT2 is the sole source of cholesterol esters for VLDL and chylomicron assembly. VLDL production is controlled primarily at the level of presecretory degradation. Recently, it was discovered that the LDL receptor modulates VLDL production through its interactions with nascent VLDL in the secretory pathway.

ApoAV Reduces Plasma Triglycerides by Inhibiting Very Low Density Lipoprotein-Triglyceride (VLDL-TG) Production and Stimulating Lipoprotein Lipase-mediated VLDL-TG Hydrolysis

“…VLDL assembly is a multicompartemental process proceeding in two major steps (20). First, apoB is lipidated during the translation of its mRNA in the rough ER.…”

Thermal Transitions in Human Very-Low-Density Lipoprotein: Fusion, Rupture, and Dissociation of HDL-like Particles

“…HDL are anti-atherogenic, LDL are pro-atherogenic, and VLDL are not only direct metabolic precursors of LDL but also an independent risk factor for atherosclerosis (1)(2)(3)(4)(5)(6)(7)(8). VLDL are the major carriers of triacylglycerides (TG) in plasma.…”

Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins

“…VLDL assembly is currently believed to occur in two different stages, both of which require an enzyme called microsomal triglyceride transfer protein (MTP) (10). In the first stage, MTP transfers triglyceride from cytosolic lipid droplets or the endoplasmic reticulum (ER) to nascent apolipoprotein (apo) B-100, a 540-kDa protein that confers structural integrity to VLDL (11).…”

“…In the second stage, apoB-containing VLDL precursor particles fuse with triglyceride droplets in the ER/ Golgi luminal compartment (10), a step facilitated by apoE, another major protein component of VLDL (14). Additional triglyceride is transferred by MTP from cytosolic lipid droplets to the luminal compartment in amounts sufficient to promote VLDL assembly in this stage (10). In humans and mice, a genetic defect in MTP severely reduces VLDL secretion (15,16).…”