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

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 8

Incubation of McA cells with OA results in dose-related increases in intracellular degradation of apoB100 by nonproteasomal pathways.

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Incubation of McA cells with OA results in dose-related increases in int...
McA cells were incubated in the presence or absence of OA for 16 hours; cells were pulse labeled with [35S]methionine for 20 minutes and chased for 90 minutes. Samples were taken every 15 minutes and processed by immunoprecipitation and 4% SDS-PAGE. The quantity of protein in the cell lysates at the 15-minute chase time point was taken as 100% of newly synthesized apoB100 (A), apoB48 (B), or albumin (C). Data are mean ± SD normalized to cells incubated without OA. *P < 0.05 vs. control; n = 3 for each condition. Incubations with increasing concentrations of OA were associated with a parabolic effect on intracellular degradation and secretion of apoB100; there were no effects of increasing OA on degradation or secretion of apoB48 or albumin. (D). McA cells were incubated for 16 hours with no OA, 0.4 mM OA, or 1.2 mM OA in the absence or presence of lactacystin and then radiolabeled for 2 hours Lactacystin did not alter the parabolic effect of increasing concentrations of OA on apoB100 secretion.