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

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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

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Figure 6

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DHA-induced ApoB100 degradation in primary rat hepatocytes also requires...
DHA-induced ApoB100 degradation in primary rat hepatocytes also requires the increased generation of lipid peroxides. Primary rat hepatocytes were maintained overnight in modified Waymouth’s medium (Figure 1). Two different treatment protocols were subsequently followed: (A) Cells were incubated for 1 hour with either BSA or DHA/BSA, followed by 3 hours of incubation with BSA, DHA/BSA, DHA/BSA plus 100 ∝M DFX, or DHA/BSA plus 200 ∝M vitamin E. Shown are the TBARS assay results. *P < 0.01 vs. DHA. (B) Cells were pretreated with BSA or DHA/BSA for 2 hours, followed by pulse labeling and a chase period up to 120 minutes. DFX or vitamin E was added as in Figure 2B. The recovery of total labeled ApoB100 was determined as in Figure 1. *P < 0.01 vs. DHA.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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