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.

Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage

“…The degradation of both APOB and misfolded fibrinogens follows the ubiquitination proteasome pathway [ 27 , 28 ], which requires dislocation and retrotranslocation of the aberrant proteins towards the cytoplasm with the cooperation of endoplasmic reticulum-associated degradation (ERAD) proteins. ERAD are found in association with cytoplasmic lipid degradation complexes [ 23 , 29 ]. In addition to the ERAD pathway, the excess of aggregated fibrinogen mutants is degraded via autophagy [ 16 ].…”

The RNA-binding protein vigilin regulates VLDL secretion through modulation of Apob mRNA translation

“…As the core protein of VLDL and LDL particles, apoB is of paramount importance for maintaining triglyceride balance within the liver. Although regulation of apoB by post-translational degradation pathways within the ER, post-ER 36 , and by autophagy 37 38 is well established, translational regulatory mechanisms that govern apoB expression are poorly understood 39 . Our study demonstrates that vigilin is a major determinant of apoB translation and VLDL secretion by hepatocytes without affecting VLDL clearance and therefore a regulator of net triglyceride secretion by the liver.…”

Enriching Diet with n-3 PUFAs to Help Prevent Cardiovascular Diseases in Healthy Adults: Results from Clinical Trials

“…LDL concentrations seem to be less responsive to PUFA supplementation compared to TGCs and results on oxidized LDL are also poorly consistent. Lipoprotein secretion in healthy people undergoes well-regulated mechanisms in order to ensure an optimal lipid homeostasis [ 70 ] and quantitative data on the regulation of plasma lipids in subjects showing no alterations in lipid formula are sometimes difficult to be interpreted. Therefore, it seems fair to assume that even weak changes after PUFA intake may be substantial.…”