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Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents
Tsuguhito Ota, … , Constance Gayet, Henry N. Ginsberg
Tsuguhito Ota, … , Constance Gayet, Henry N. Ginsberg
Published December 3, 2007
Citation Information: J Clin Invest. 2008;118(1):316-332. https://doi.org/10.1172/JCI32752.
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Research Article Cell biology Article has an altmetric score of 3

Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents

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Abstract

ER stress can cause hepatic insulin resistance and steatosis. Increased VLDL secretion could protect the liver from ER stress–induced steatosis, but the effect of lipid-induced ER stress on the secretion of VLDL is unknown. To determine the effect of lipids on hepatic ER stress and VLDL secretion, we treated McA-RH7777 liver cells with free fatty acids. Prolonged exposure increased cell triglycerides, induced steatosis, and increased ER stress. Effects on apoB100 secretion, which is required for VLDL assembly, were parabolic, with moderate free fatty acid exposure increasing apoB100 secretion, while greater lipid loading inhibited apoB100 secretion. This decreased secretion at higher lipid levels was due to increased protein degradation through both proteasomal and nonproteasomal pathways and was dependent on the induction of ER stress. These findings were supported in vivo, where intravenous infusion of oleic acid (OA) in mice increased ER stress in a duration-dependent manner. apoB secretion was again parabolic, stimulated by moderate, but not prolonged, OA infusion. Inhibition of ER stress was able to restore OA-stimulated apoB secretion after prolonged OA infusion. These results suggest that excessive ER stress in response to increased hepatic lipids may decrease the ability of the liver to secrete triglycerides by limiting apoB secretion, potentially worsening steatosis.

Authors

Tsuguhito Ota, Constance Gayet, Henry N. Ginsberg

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Figure 3

OA or IL induces phosphorylation of eIF2α in McA cells.

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OA or IL induces phosphorylation of eIF2α in McA cells.
(A) Incubation o...
(A) Incubation of McA cells for 3 or 6 hours with OA (0.4 mM) or IL (500 mg/dl) did not significantly induce phosphorylation of eIF2α. (B) Phosphorylation of eIF2α was significantly increased by incubation with either OA (0.4 mM) or IL (500 mg/dl) for 16 hours without a change in total eIF2α protein level. ER stress was also induced by a 3-hour treatment with tunicamycin (5 μg/ml) as a positive control. Lanes were run on the same gel but were noncontiguous. Data are mean ± SD normalized to cells incubated without OA or IL (n = 3 for each condition); *P < 0.01 versus control incubations.

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

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Referenced in 8 patents
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