Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • 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
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Insig: a significant integrator of nutrient and hormonal signals
Alan D. Attie
Alan D. Attie
Published April 15, 2004
Citation Information: J Clin Invest. 2004;113(8):1112-1114. https://doi.org/10.1172/JCI21450.
View: Text | PDF
Commentary

Insig: a significant integrator of nutrient and hormonal signals

  • Text
  • PDF
Abstract

Lipogenesis is regulated by sterols and by insulin through the regulated expression and activation of the sterol regulatory element–binding proteins (SREBPs). A new study shows one way in which sterol and insulin regulation can be decoupled. In transgenic mice overexpressing a protein that regulates SREBP activation, lipogenesis is more sensitive to cholesterol and less sensitive to insulin.

Authors

Alan D. Attie

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Integration of metabolic signals at the ER membrane. (A) During fasting,...
Integration of metabolic signals at the ER membrane. (A) During fasting, expression of the SREBP-1c precursor (pSREBP-1c) is reduced. Insig-2a is expressed and binds to SCAP, causing retention of a very low amount of pSREBP-1c in the ER in the presence of sterols. (B) Upon refeeding, insulin increases the expression of pSREBP-1c and decreases the expression of Insig-2a. The low abundance of both Insig-1 and Insig-2a leads to greatly increased processing of pSREBP-1c to mature SREBP-1c (mSREBP-1c), leading to a lipogenesis rate that is more than tenfold higher than that of the basal state, which represents an “overshoot.” The increased level of mSREBP-1c promotes expression of Insig-1. At a critical stoichiometry relative to SCAP, Insig-1 restores sterol-mediated regulation of pSREBP-1c processing. The lipogenesis rate then returns to the original basal level. (C) With transgenic overexpression of Insig-1, the cycling of lipogenesis between the fed and fasted states is dampened. The high ratio of Insig-1 to SCAP causes retention of pSREBP-1c in the ER. Fasted mice have a modest additional drop in lipogenesis due to the reduction of pSREBP-1c expression and increased Insig-2a levels. (D) With refeeding, the transgenic mice express extremely low levels of pSREBP-1c due to their inability to produce enough mSREBP-1c to drive the transcription of the pSREBP-1c gene. The persistently elevated level of Insig-1 abolishes the dramatic “overshoot” in lipogenesis seen in the wild-type refed mice but still mediates an enhanced sensitivity of pSREBP-1c processing to sterols.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts