title: Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion.
abstract: Apolipoprotein B (apoB) is the main protein component of very low density lipoprotein (VLDL) and is necessary for the assembly and secretion of these triglyceride (TG)-rich particles. Following release from the liver, VLDL is converted to low density lipoprotein (LDL) in the plasma and increased production of VLDL can therefore play a detrimental role in cardiovascular disease. Increasing evidence has helped to establish VLDL assembly as a target for the treatment of dyslipidemias. Multiple factors are involved in the folding of the apoB protein and the formation of a secretion-competent VLDL particle. Failed VLDL assembly can initiate quality control mechanisms in the hepatocyte that target apoB for degradation. ApoB is a substrate for endoplasmic reticulum associated degradation (ERAD) by the ubiquitin proteasome system and for autophagy. Efficient targeting and disposal of apoB is a regulated process that modulates VLDL secretion and partitioning of TG. Emerging evidence suggests that significant overlap exists between these degradative pathways. For example, the insulin-mediated targeting of apoB to autophagy and postprandial activation of the unfolded protein response (UPR) may employ the same cellular machinery and regulatory cues. Changes in the quality control mechanisms for apoB impact hepatic physiology and pathology states, including insulin resistance and fatty liver. Insulin signaling, lipid metabolism and the hepatic UPR may impact VLDL production, particularly during the postprandial state. In this review we summarize our current understanding of VLDL assembly, apoB degradation, quality control mechanisms and the role of these processes in liver physiology and in pathologic states.
authors.affiliation: Biochemistry & Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Fisher
authors.affiliation: Biochemistry & Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lake
authors.affiliation: Biochemistry & Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors.forename: Roger S
authors.initials: RS
authors.lastname: McLeod
keywords: apolipoprotein B; autophagy; proteasome; steatosis; ubiquitin; very low density lipoprotein