Cited by 79Cholesterol and Lipid MetabolismCancer, Lipids, and MetabolismLipid metabolism and biosynthesis

The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP

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Janowski, Bethany A.·2002·Proceedings of the National Academy of Sciences

Abstract

Oxysterols regulate cholesterol homeostasis through liver X receptor (LXR; cholesterol-lowering)- and sterol regulatory element-binding protein (SREBP; cholesterol-raising)-mediated signaling pathways. Previously we reported that the hypocholesterolemic agent LY295427 (4α-allylcholestan-3α-ol) reverses oxysterol-mediated suppression of SREBP processing. We now report that LY295427 increases expression of insulin-induced gene-1 (INSIG-1) and restores SREBP processing in cells treated with oxysterols. In cells overexpressing the INSIG-1 gene, by contrast, SREBP processing is suppressed and oxysterol regulation is disrupted. SREBP processing is not restored by addition of LY295427, but is restored by increasing the levels of SREBP cleavage-activating protein (SCAP). These findings suggest that the INSIG-1 protein alters sterol balance by modulating SREBP processing jointly with SCAP. To test whether the action of oxysterols on SREBP processing is mediated through endogenous INSIG-1 protein, we used RNAi to lower the expression of the INSIG-1 gene, and found that reduced INSIG-1 protein levels caused the loss of SREBP regulation by oxysterols. We conclude that: ( i ) INSIG-1 gene expression is suppressed by oxysterols; ( ii ) LY295427 treatment counters the suppressive effects of oxysterols on SREBP processing, resulting in the expression of the INSIG-1 gene; and ( iii ) INSIG-1 gene expression affects SREBP processing. Taken together, these data suggest that INSIG-1 plays a critical role in regulating cholesterol concentrations in the cell.

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Authors
Janowski, B. A.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Janowski, Bethany A.
Venue
Proceedings of the National Academy of Sciences
Published
2002-09-19
Volume
99
Issue
20
Pages
12675-12680
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W1984997497
Cited by
79
References
26
Citations by year
2026: 2 · 2025: 2 · 2023: 1 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 3 · 2013: 2
FWCI
8.27
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (HL20948)
  • National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
INSIG1, cholesterol homeostasis, oxysterols, SCAP, liver X receptor, hypocholesterolemic agents, SREBP, sterol balance
MeSH terms
Anticholesteremic Agents, Cell Line, Cell Nucleus, Cholestanols, Cholesterol, Cloning, Molecular, DNA-Binding Proteins, Gene Expression Regulation, Homeostasis, Humans, Membrane Proteins, Models, Biological, Proteins, RNA, Steroids, Time Factors, Transcription Factors, Transfection, Immunoblotting, Blotting, Northern, Signal Transduction, Up-Regulation, DNA, Complementary, Oligonucleotide Array Sequence Analysis, CCAAT-Enhancer-Binding Proteins, Intracellular Signaling Peptides and Proteins, Sterol Regulatory Element Binding Protein 1

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