The Role of Factors that Regulate the Synthesis and Secretion of Very-Low-Density Lipoprotein by Hepatocytes

Abstract

Lipoproteins are particles that contribute to overall metabolic homeo-stasis by transporting hydrophobic lipids in the blood plasma to and from different tissues in the body. Very-low-density lipoprotein (VLDL) is the principal vehicle for the transport of endogenous triglyceride (TG), and, ultimately, through its metabolic product, low-density lipoprotein (LDL), of cholesterol as well. It is synthesized mainly in hepatocytes, with small amounts also being produced by enterocytes in the fasting state. The mechanism of VLDL assembly is complex and is regulated at different levels by a variety of factors. The main structural protein of VLDL is called apolipoprotein B-100 (Apo B). Apo B formation and degradation therefore represent two major points of regulation of VLDL secretion. Hepatic levels of lipids such as phosphatidylcholine (PC), cholesteryl ester (CE), fatty acids (FA), and TG also affect VLDL synthesis. There are different views as to the specific mechanism by which each lipid class affects VLDL particle formation. In general, PC appears to promote the translocation of apo B from the cytosol to the lumen of the endoplasmic reticulum, a step that is crucial in the early stages of VLDL assembly. Apo B degradation is suppressed, and therefore VLDL secretion is enhanced, in the presence of elevated CE levels. For TG to be incorporated into the lipoprotein, it requires the action of a protein called microsomal triglyceride transfer protein (MTP). MTP might have a preference for TG comprised of FA with a certain degree of saturation. It becomes apparent that changes in diet that are accompanied by variations in the type of fats that are ingested affect VLDL formation and secretion. Regulation also occurs post-prandially in response to elevations in plasma insulin levels. Acute elevations in insulin inhibit VLDL secretion by promoting the degradation of apo B. This action is consistent with insulin's anabolic properties as it allows for the hepatic storage of lipid rather than for its distribution in VLDL to other tissues for fuel. Many studies have attempted to unravel the mechanisms of VLDL formation and secretion. The fact that so many factors are involved complicates the issue. The purpose of this article is to describe the relationship between different factors involved in VLDL assembly and secretion so that a better understanding of its metabolic regulation may be achieved.