Glucose-dependent de Novo Lipogenesis in B Lymphocytes

Dufort, Fay J.; Gumina, Maria R.; Ta, Nathan L.; Tao, Yongzhen; Heyse, Shannon A.; Scott, David A.; Richardson, Adam D.; Seyfried, Thomas N.; Chiles, Thomas C.

doi:10.1074/jbc.m114.551051

Cited by 161Cancer, Lipids, and MetabolismLipid metabolism and biosynthesisT-cell and B-cell Immunology

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

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Dufort, Fay J., Gumina, Maria R., Ta, Nathan L., Tao, Yongzhen, Heyse, Shannon A., Scott, David A., Richardson, Adam D., Seyfried, Thomas N. +1 more·2014·Journal of Biological Chemistry

DOI 10.1074/jbc.m114.551051PMC PMC3945362

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Abstract

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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Plasma cells contain more phospholipids than naïve B cells.
“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
Plasma cell differentiation requires mitochondrial citrate to be converted to acetyl-CoA and oxaloacetate in the cytoplasm.
“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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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.
ORCID: Ta, Nathan L.
Tao, Yongzhen
Scott, David A.
Richardson, Adam D.
Seyfried, Thomas N.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2014-03
Volume: 289
Issue: 10
Pages: 7011-7024
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m114.551051
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 2394 d)
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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Glucose-dependent de Novo Lipogenesis in B Lymphocytes

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