Phospholipid transfer protein deficiency impairs apolipoprotein-B secretion from hepatocytes by stimulating a proteolytic pathway through a relative deficiency of vitamin E and an increase in intracellular oxidants.
Genetic deficiency of the plasma phospholipid transfer protein (PLTP) in mice unexpectedly causes a substantial impairment in liver secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins. To explore the mechanism, we examined the three known pathways for hepatic apoB secretory control, namely endoplasmic reticulum (ER)/proteasome-associated degradation (ERAD), post-ER pre-secretory proteolysis (PERPP), and receptor-mediated degradation, also known as re-uptake. First, we found that ERAD and cell surface re-uptake were not active in PLTP-null hepatocytes. Moreover, ER-to-Golgi blockade by brefeldin A, which enhances ERAD, equalized total apoB recovery from PLTP-null and wild-type cells, indicating that the relevant process occurs post-ER. Second, because PERPP can be stimulated by intracellular reactive oxygen species (ROS), we examined hepatic redox status. Although we found previously that PLTP-null mice exhibit elevated plasma concentrations of vitamin E, a lipid anti-oxidant, we now discovered that their livers contain significantly less vitamin E and significantly more lipid peroxides than do livers of wild-type mice. Third, to establish a causal connection, the addition of vitamin E or treatment with an inhibitor of intracellular iron-dependent peroxidation, desferrioxamine, abolished the elevation in cellular ROS as well as the defect in apoB secretion from PLTP-null hepatocytes. Overall, we conclude that PLTP deficiency decreases liver vitamin E content, increases hepatic oxidant tone, and substantially enhances ROS-dependent destruction of newly synthesized apoB via a post-ER process. These findings are likely to be broadly relevant to hepatic apoB secretory control in vivo.
Jiang
Xian-Cheng
XC
State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA. Xian-Cheng_Jiang@downstate.edu
Li
Zhiqiang
Z
Liu
Ruijie
R
Yang
Xiao Ping
XP
Pan
Meihui
M
Lagrost
Laurent
L
Fisher
Edward A
EA
Williams
Kevin Jon
KJ
D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016877:Oxidants / Q000096:biosynthesis*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014811:Vitamin E Deficiency / Q000235:genetics / Q000378:metabolism*
D001055:Apolipoproteins B; D008565:Membrane Proteins; D016877:Oxidants; D049294:Phospholipid Transfer Proteins; D010447:Peptide Hydrolases