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 11

Stimulation of the secretion of apoB100 by 6-hour infusions of 6 mM OA is lost after infusion of OA for 9 hours but rescued after pretreatment of mice with PBA.

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Stimulation of the secretion of apoB100 by 6-hour infusions of 6 mM OA i...
C57BL/6J mice were infused with saline (white bars) or 6 mM OA in albumin (gray bars) intravenously for 6 or 9 hours, and both Triton WR1339 and [35S]methionine were injected into the mice at the end of each infusion to measure the secretion of newly synthesized apoB48 and apoB100. (A) Infusion of OA for 6 hours significantly increased the secretion of both apoB100 and apoB48 secretion into the bloodstream 1 hour after Triton injection compared with saline. (B) Infusion of OA for 9 hours did not increase either apoB100 or apoB48 secretion compared with saline. (C) PBA or water was administered orally to C57BL/6J mice for 7 days. After 9 hours of OA infusion, the PBA-treated mice showed an increase in apoB100 secretion compared with the nontreated mice. Data are mean ± SD normalized to saline-infused livers (for 6-hour infusions: n = 9 and 11 for saline and OA, respectively; for 9-hour infusions: n = 4/group; for 9-hour infusion with or without PBA: n = 6/group). *P < 0.05 versus saline; **P < 0.01 versus without PBA treatment.