Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
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

  • Text
  • PDF
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

×

Figure 5

Lipid loading–induced ER stress has a parabolic effect on apoB100 secretion in McA cells.

Options: View larger image (or click on image) Download as PowerPoint
Lipid loading–induced ER stress has a parabolic effect on apoB100 secret...
(A). McA cells were preincubated with 0.4, 0.8, or 1.2 mM of OA for 3, 6, or 16 hours, incubated for 2 hours in methionine/cysteine-free DMEM, and then labeled with [35S]methionine for 2 hours, the latter 2 incubations still in the presence of OA. There was a time and dose-dependent change from stimulation to inhibition of apoB100 secretion. (B) At the same doses, there were no effects of OA on the secretion of apoB48, apoA-I, or albumin at any duration of preincubation. (C) Using the same preincubation and incubation protocol, 1.6 mM OA decreased apoB100, apoB48, albumin, and apoA-I secretion. (D) McA cells were preincubated with 100, 500, or 1,000 mg/dl IL for 16 hours, followed by the protocol described in A with IL present during the last 2 steps. There was a dose-dependent increase in ER stress, as indicated by increasing levels of GRP78 protein. (E) 100 mg/dl IL stimulated apoB100 secretion, whereas 500 mg/dl IL did not. Incubation with 1,000 mg/dl IL actually inhibited apoB100 secretion. Intralipid, at the doses used, had no effects on apoB48, albumin, or apoA-I secretion. (F) TCA precipitable radioactivity was unaffected at concentrations of 0.4, 0.8, or 1.2 mM OA. However, a 16-hour preincubation with 1.6 mM OA did reduce TCA-precipitable radioactivity by about 30%. None of the doses of IL that were used affected TCA-precipitable radioactivity. All data are mean ± SD normalized to cells incubated without OA or IL (n = 3 for each condition); *P < 0.05, **P < 0.01 versus control incubations.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 8 patents
157 readers on Mendeley
See more details