Hepatic synthesis of lipoproteins and apolipoproteins

We have attempted to review new information concerning the regulation of the secretion of three major apolipoproteins that are synthesized in the liver: apoB, apoA-I, and apoE. ApoB, which is a large protein involved in the transport of triglyceride and cholesterol from the liver to the peripheral tissues, appears not to be regulated on a short-term basis at the transcriptional level. Rather, once synthesized, this protein, which is unique in its intracellular transport in the secretory pathway, is subjected to post-translational regulation, which is dependent on the lipid status of the cell. Assembly of nascent apoB-containing LPs begins in the ER. If core lipids, whether triglyceride or cholesteryl ester, are limiting, then apoB will be rapidly degraded, most likely in the ER compartment. However, if one or both of the core lipids are available in adequate quantities, then apoB will be protected in the ER, and more apoB, in the form of an apoB-containing LP (whether VLDL or a smaller particle) will be secreted by the hepatocyte. Addition of surface lipids, mainly phospholipids or free cholesterol, probably occurs in the Golgi. A further mechanism that regulates the secretion of apoB-containing LPs may involve rapid reuptake of newly secreted particles. The regulation of the secretion of apoA-I by liver is very different from that of apoB. Although apoA-I is also synthesized on attached ribosomes and becomes cotranslationally or post-translationally associated with the RER membrane, it is transported to the Golgi much more rapidly than apoB. In the Golgi nascent HDL particles are formed, but it is also likely that apoA-I is secreted by the hepatocyte in a lipid-poor form. Unlike apoB, apoA-I, after synthesis, is quantitatively secreted by the cell. Regulation of apoA-I secretion therefore occurs primarily at the transcriptional or post-transcriptional level. Which factors regulate apoA-I secretion are still under active investigation, but it appears that estrogens, and possibly alcohol, can modulate apoA-I synthesis, and therefore apoA-I secretion. ApoE is synthesized in several cell types and therefore may play a wide variety of physiologic roles. In liver, apoE secretion appears to be regulated at the transcriptional, post-transcriptional, and possibly at the post-translational levels. The nutritional factors that influence apoE secretion are dietary cholesterol, carbohydrate, and the fasting condition. Much less is known about the intracellular transport of apoE than about that of apoB or apoAI. Immunocytochemical observations indicated that apoE is not associated with VLDL particles in the Golgi, but it is possible that apoE, like apoAI, is secreted on nascent HDL or in a lipid-poor form. After secretion, apoE rapidly associates with either nascent HDL or VLDL.