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Cited by 121Lipid metabolism and biosynthesisLipid metabolism and disordersCancer, Lipids, and Metabolism

Partitioning of MLX-family transcription factors to lipid droplets regulates metabolic gene expression

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Mejhert, Niklas, Kuruvilla, Leena, Gabriel, Katlyn R., Elliott, Shane D., Guie, Marie-Aude, Wang, Huajin, Lai, Zon Weng, Lane, Elizabeth A. +4 more·2020·Molecular Cell
DOI 10.1016/j.molcel.2020.01.014PMC PMC7397554
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Abstract

Lipid droplets (LDs) store lipids for energy and are central to cellular lipid homeostasis. The mechanisms coordinating lipid storage in LDs with cellular metabolism are unclear but relevant to obesity-related diseases. Here we utilized genome-wide screening to identify genes that modulate lipid storage in macrophages, a cell type involved in metabolic diseases. Among ∼550 identified screen hits is MLX, a basic helix-loop-helix leucine-zipper transcription factor that regulates metabolic processes. We show that MLX and glucose-sensing family members MLXIP/MondoA and MLXIPL/ChREBP bind LDs via C-terminal amphipathic helices. When LDs accumulate in cells, these transcription factors bind to LDs, reducing their availability for transcriptional activity and attenuating the response to glucose. Conversely, the absence of LDs results in hyperactivation of MLX target genes. Our findings uncover a paradigm for a lipid storage response in which binding of MLX transcription factors to LD surfaces adjusts the expression of metabolic genes to lipid storage levels.

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  • APOE was identified in subsequent studies of the lipid droplet proteome in mouse liver and THP-1 macrophages.

    “APOE was identified in subsequent studies of the LD proteome in mouse liver and THP-1 macrophages (Krahmer et al., 2018; Mejhert et al., 2020).”

    From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Mejhert et al., 2020

    The Results section, “Identification of LD Proteins in Human THP-1 Macrophages” (page unavailable), reports an LD-enriched proteomic analysis of THP-1 cells. The passages name several identified proteins but do not name APOE, so our copy does not establish that this study identified APOE in the LD proteome. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • 2099 overlapping proteins were identified and considered as LD-resident proteins by cross-referencing with six known lipid droplet proteomes.

    “Upon cross-referencing our database with the six others, 2099 overlapping proteins were identified and considered as LD-resident proteins.”

    From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Mejhert et al., 2020

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Both cell type and cellular environment modulate the lipid droplet proteome and lipidome.

    “Importantly, both cell type and cellular environment modulate the lipid droplet proteome and lipidome3–9.”

    From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [9]

    The Results (Systematic Classification of Regulators of Lipid Storage in Human Macrophages; page unavailable) report lipid droplets containing triglycerides and cholesterol esters after lipoprotein loading, and the Methods distinguish loading conditions that induce different lipid storage. The Results (Transcription Factor MLX Binds to LDs; page unavailable) show that oleate-induced droplet formation affects MLX localization. The paper does not establish the broader claim that both cell type and cellular environment modulate both the droplet proteome and lipidome. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A few of these non-canonical functions have been associated with lipid droplets in other organisms like Drosophila melanogaster and in other cell systems.

    “Interestingly, a few of these non-canonical functions have been associated with lipid droplets in other organisms like Drosophila melanogaster46,66 and in other cell systems3,9.”

    From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [9]

  • Genetic knockdown studies show RUFY2 influences lipid droplet morphology and distribution.

    “Genetic knockdown studies show RUFY2 influences lipid droplet morphology and distribution9,41, hinting at a potential link between vesicle trafficking defects69 and altered lipid biology in astrocytes, particularly in neurodegenerative contexts.”

    From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [9]

    The Results section describes an RNAi screen measuring lipid-droplet size, shape, and dispersion, but the passages available from our copy do not identify RUFY2 as a hit or report its knockdown phenotype. Searches for RUFY2 and for RUFY2 knockdown effects on lipid droplets found no passage establishing the claimed effect. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Mejhert, N., Kuruvilla, L., Gabriel, K. R., Elliott, S. D., Guie, M.-A., Wang, H., Lai, Z. W., Lane, E. A., Christiano, R., Danial, N. N., Farese, R. V., & Walther, T. C.
Affiliations
  • Harvard University (US)
  • Yale University (US)
  • Howard Hughes Medical Institute (US)
  • Broad Institute (US)
Corresponding author
  • Farese, Robert V.
  • Walther, Tobias C.
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2020-03
Volume
77
Issue
6
Pages
1251-1264.e9
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2020.01.014
PMC
PMC7397554
OpenAlex
W3005380228
Cited by
121
References
8
Citations by year
2026: 17 · 2025: 22 · 2024: 16 · 2023: 18 · 2022: 20 · 2021: 22 · 2020: 6
FWCI
7.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • H2020 Marie Skłodowska-Curie Actions
  • G. Harold and Leila Y. Mathers Foundation (SUM159)
  • National Institutes of Health (5R01GM124348, R01GM097194)
  • Merck
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
lipid droplets, amphipathic helix, macrophages, fat deposition, glucose detection, metabolic gene expression, obesity, lipid homeostasis, transcriptional regulation
MeSH terms
Cells, Cultured, Gene Expression Regulation, Genetic Testing, Glucose, Humans, Macrophages, Protein Binding, Transcription, Genetic, Proteome, RNA, Small Interfering, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Lipid Droplets

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