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
Open accessAbstract
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.
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- Authors
- Jiang, X.-C., Li, Z., Liu, R., Yang, X. P., Pan, M., Lagrost, L., Fisher, E. A., & Williams, K. J.
- Affiliations
- SUNY Downstate Health Sciences University (US)
- New York University (US)
- Inserm (FR)
- Thomas Jefferson University (US)
- Corresponding author
- Jiang, Xian-Cheng
- Williams, Kevin Jon
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 280
- Issue
- 18
- Pages
- 18336-18340
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2013778226
- Cited by
- 102
- References
- 34
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 3 · 2016: 2 · 2015: 6 · 2014: 1 · 2013: 2 · 2012: 6
- FWCI
- 12.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- American Heart Association
- National Institutes of Health (HL56984)
- National Heart, Lung, and Blood Institute (HL-69817, P50HL056984, HL 58541, R01HL069817, HL 64735, R01HL064735, HL 56984, R01HL058541)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- phospholipid transfer protein, apolipoprotein B secretion, hepatocytes, vitamin E deficiency, reactive oxygen species, lipid peroxidation, ER-associated degradation, deferoxamine, atherogenic lipoproteins
- MeSH terms
- Animals, Apolipoproteins B, Cells, Cultured, Humans, Intracellular Fluid, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Peptide Hydrolases, Vitamin E Deficiency, Oxidants, Mice, Knockout, Hepatocytes, Phospholipid Transfer Proteins, Mice
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