Glucose-dependent de Novo Lipogenesis in B Lymphocytes A REQUIREMENT FOR ATP-CITRATE LYASE IN LIPOPOLYSACCHARIDE-INDUCED DIFFERENTIATION

Background: The metabolic requirements underlying B lymphocyte differentiation are poorly understood. Results: Differentiation is accompanied by glucose metabolism into fatty acid and cholesterol synthesis, mediated by ATP-citrate lyase (ACLY). Conclusion: ACLY-dependent lipogenesis is required for several phenotypic changes defining plasma cell differentiation. Significance: This study proposes a critical role for ACLY coupled glucose-dependent de novo lipogenesis in LPS-induced B lymphocyte differentiation. 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.