Cited by 194Lipid metabolism and biosynthesisCancer, Lipids, and MetabolismCholesterol and Lipid Metabolism

The SREBP Pathway in Drosophila

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Seegmiller, Adam C., Dobrosotskaya, Irina, Goldstein, Joseph L., Ho, Y.K., Brown, Michael S., Rawson, Robert B.·2002·Developmental Cell

Abstract

In mammals, synthesis of cholesterol and unsaturated fatty acids is controlled by SREBPs, a family of membrane-bound transcription factors. Here, we show that the Drosophila genome encodes all components of the SREBP pathway, including a single SREBP (dSREBP), SREBP cleavage-activating protein (dSCAP), and the two proteases that process SREBP at sites 1 and 2 to release the nuclear fragment. In cultured Drosophila S2 cells, dSREBP is processed at sites 1 and 2, and the liberated fragment increases mRNAs encoding enzymes of fatty acid biosynthesis, but not sterol or isoprenoid biosynthesis. Processing requires dSCAP, but is not inhibited by sterols as in mammals. Instead, dSREBP processing is blocked by palmitic acid. These findings suggest that the ancestral SREBP pathway functions to maintain membrane integrity rather than to control cholesterol homeostasis.

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Crossref · 10.1016/s1534-5807(01)00119-8

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  • Homologs of SREBPs do not respond to changes in cholesterol, but rather changes in palmitate and/or phospholipids.

    “It has been previously shown that the homologs of SREBPs do not respond to changes in cholesterol, but rather changes in palmitate and/or phospholipids (39,40).”

    From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [40]

    The Results report that palmitate reduced nuclear dSREBP in Drosophila S2 cells, whereas a cholesterol-containing sterol mixture failed to do so. The Discussion proposes that palmitic acid or a lipid derived from it regulates this pathway, but does not establish phospholipids as the signal. The claim also generalizes beyond the Drosophila homolog studied here. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • D. melanogaster is a cholesterol auxotroph and activation of SREBP is regulated by reduced levels of palmitate and/or phospholipids.

    “D. melanogaster is a cholesterol auxotroph and activation of SREBP is regulated by reduced levels of palmitate and/or phospholipids.”

    From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [40]

    The paper says insects require dietary sterols, supporting the description of D. melanogaster as a cholesterol auxotroph. The Results and Discussion show that added palmitate inhibits dSREBP processing in cultured Drosophila cells, but the Discussion says it is not clear whether palmitate itself or a more complex lipid, possibly a phospholipid, is responsible. It does not establish that reduced phospholipid levels activate SREBP. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Authors
Seegmiller, A. C., Dobrosotskaya, I., Goldstein, J. L., Ho, Y. K., Brown, M. S., & Rawson, R. B.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Goldstein, Joseph L.
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2002-02
Volume
2
Issue
2
Pages
229-238
ISSN
1534-5807 (ISSN-L)
OpenAlex
W1993125269
Cited by
194
References
45
Citations by year
2026: 6 · 2025: 2 · 2024: 12 · 2023: 10 · 2022: 8 · 2021: 3 · 2020: 11 · 2019: 8 · 2018: 6 · 2017: 7 · 2016: 3 · 2015: 11 · 2014: 3 · 2013: 5 · 2012: 2
FWCI
6.85
Type
journal article
Language
en
Open access
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
  • National Institute of General Medical Sciences (GM-08014, T32GM008014)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
SREBP pathway, SCAP, palmitic acid, fatty acid synthesis, sterol biosynthesis, isoprenoid biosynthesis, membrane integrity, cholesterol homeostasis, Drosophila, S2 cells, transcriptional regulation
MeSH terms
Animals, Cell Line, DNA-Binding Proteins, Drosophila, Fatty Acids, Humans, Membrane Proteins, Mutation, Peptide Fragments, Protein Processing, Post-Translational, RNA, Double-Stranded, RNA, Messenger, Sterols, Transcription Factors, Blotting, Western, Polymerase Chain Reaction, Sequence Homology, Amino Acid, Pyruvic Acid, Palmitic Acid, CCAAT-Enhancer-Binding Proteins, Intracellular Signaling Peptides and Proteins, Sterol Regulatory Element Binding Protein 1

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