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Glucose-dependent de Novo Lipogenesis in B Lymphocytes
Open accessAbstract
Bacterially derived lipopolysaccharide (LPS) stimulates naive B lymphocytes to differentiate into immunoglobulin (Ig)-secreting plasma cells. Differentiation of B lymphocytes is characterized by a proliferative phase followed by expansion of the intracellular membrane secretory network to support Ig production. A key question in lymphocyte biology is how naive B cells reprogram metabolism to support de novo lipogenesis necessary for proliferation and expansion of the endomembrane network in response to LPS. We report that extracellularly acquired glucose is metabolized, in part, to support de novo lipogenesis in response to LPS stimulation of splenic B lymphocytes. LPS stimulation leads to increased levels of endogenous ATP-citrate lyase (ACLY), and this is accompanied by increased ACLY enzymatic activity. ACLY produces cytosolic acetyl-CoA from mitochondrially derived citrate. Inhibition of ACLY activity in LPS-stimulated B cells with the selective inhibitor 2-hydroxy-N-arylbenzenesulfonamide (compound-9; C-9) blocks glucose incorporation into de novo lipid biosynthesis, including cholesterol, free fatty acids, and neutral and acidic phospholipids. Moreover, inhibition of ACLY activity in splenic B cells results in inhibition of proliferation and defective endomembrane expansion and reduced expression of CD138 and Blimp-1, markers for plasma-like B cell differentiation. ACLY activity is also required for LPS-induced IgM production in CH12 B lymphoma cells. These data demonstrate that ACLY mediates glucose-dependent de novo lipogenesis in response to LPS signaling and identify a role for ACLY in several phenotypic changes that define plasma cell differentiation.
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“Recent studies have suggested that plasma cells produce increased levels of phospholipids when compared to naïve B cells, and plasma cell differentiation is dependent on mitochondrial citrate conversion to acetyl-CoA and oxaloacetate in the cytoplasm (Dufort et al., 2014; Fagone et al., 2007).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as Dufort et al., 2014
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“Recent studies have suggested that plasma cells produce increased levels of phospholipids when compared to naïve B cells, and plasma cell differentiation is dependent on mitochondrial citrate conversion to acetyl-CoA and oxaloacetate in the cytoplasm (Dufort et al., 2014; Fagone et al., 2007).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as Dufort et al., 2014
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Metadata
- Authors
- Dufort, F. J., Gumina, M. R., Ta, N. L., Tao, Y., Heyse, S. A., Scott, D. A., Richardson, A. D., Seyfried, T. N., & Chiles, T. C.
- Affiliations
- Boston College (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Chiles, Thomas C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 289
- Issue
- 10
- Pages
- 7011-7024
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3945362
- OpenAlex
- W1983616310
- Cited by
- 160
- References
- 63
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 12 · 2023: 18 · 2022: 16 · 2021: 24 · 2020: 18 · 2019: 13 · 2018: 16 · 2017: 7 · 2016: 9 · 2015: 7 · 2014: 3
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5R01AI074687)
- Topics
- 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
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- de novo lipogenesis, ATP citrate lyase, B cells, lipopolysaccharide, plasma cell differentiation, glucose metabolism, cholesterol biosynthesis, phospholipid synthesis, Blimp-1, syndecan-1, IgM production, lymphocyte metabolism
- MeSH terms
- Animals, ATP Citrate (pro-S)-Lyase, B-Lymphocytes, Cell Differentiation, Glucose, Lipopolysaccharides, Lymphocyte Activation, Mice, Inbred BALB C, Lipogenesis, Mice
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