Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production
Meihui Pan, … , Kevin Jon Williams, Edward A. Fisher
Meihui Pan, … , Kevin Jon Williams, Edward A. Fisher
Published May 1, 2004
Citation Information: J Clin Invest. 2004;113(9):1277-1287. https://doi.org/10.1172/JCI19197.
View: Text | PDF
Article Aging

Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production

Abstract

How ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) lower plasma lipid levels is incompletely understood. We previously showed that marine ω-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid) stimulate a novel pathway, post-ER presecretory proteolysis (PERPP), that degrades apolipoprotein B100 (ApoB100), thereby reducing lipoprotein secretion from liver cells. To identify signals stimulating PERPP, we examined known actions of ω-3 PUFA. In rat hepatoma or primary rodent hepatocytes incubated with ω-3 PUFA, cotreatment with the iron chelator desferrioxamine, an inhibitor of iron-dependent lipid peroxidation, or vitamin E, a lipid antioxidant, suppressed increases in thiobarbituric acid–reactive substances (TBARSs; a measure of lipid peroxidation products) and restored ApoB100 recovery and VLDL secretion. Moreover, ω-6 and nonmarine ω-3 PUFA, also prone to peroxidation, increased ApoB100 degradation via intracellular induction of TBARSs. Even without added fatty acids, degradation of ApoB100 in primary hepatocytes was blocked by desferrioxamine or antioxidant cotreatment. To extend these results in vivo, mice were infused with DHA, which increased hepatic TBARSs and reduced VLDL-ApoB100 secretion. These results establish a novel link between lipid peroxidation and oxidant stress with ApoB100 degradation via PERPP, and may be relevant to the hypolipidemic actions of dietary PUFAs, the basal regulation of ApoB100 secretion, and hyperlipidemias arising from ApoB100 overproduction.

Authors

Meihui Pan, Arthur I. Cederbaum, Yuan-Li Zhang, Henry N. Ginsberg, Kevin Jon Williams, Edward A. Fisher

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Cotreatment of McA cells with DHA and either an intracellular iron chela...
Cotreatment of McA cells with DHA and either an intracellular iron chelator or an antioxidant inhibits ApoB100 degradation and the increase in intracellular lipid peroxidation. (A) McA cells were pretreated for 1 hour with medium containing BSA or DHA/BSA complexes, followed by a 3-hour incubation in medium containing BSA, DHA/BSA, DHA/BSA plus 100 ∝M DFX, or DHA/BSA plus 120 ∝M vitamin E (vit E). Cells were then harvested for TBARS assays. *P < 0.01 vs. DHA. (B) McA cells were pretreated with BSA or DHA/BSA for 2 hours and then subjected to a pulse-chase study similar to that illustrated in Figure 1, except that DFX or vitamin E was administered 45 minutes before labeling and was present in the medium thereafter. The composite fluorogram displays representative total labeled ApoB100 recovery data, and the graph summarizes three complete experiments with each treatment applied to triplicate wells. *P < 0.01 vs. DHA. (C) A similar pulse-chase study was carried out, but DFX was replaced by the cell-impermeable iron chelator DTPA (100 ∝M). Recovery and fluorography of labeled ApoB100 were done as in Figure 1.