Glucose-dependent de Novo Lipogenesis in B Lymphocytes A REQUIREMENT FOR ATP-CITRATE LYASE IN LIPOPOLYSACCHARIDE-INDUCED DIFFERENTIATION
Glucose-dependent de Novo Lipogenesis in B Lymphocytes A REQUIREMENT FOR ATP-CITRATE LYASE IN LIPOPOLYSACCHARIDE-INDUCED DIFFERENTIATION
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DOI：
10.1074/jbc.m114.551051
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发表时间：
2014-03-07
影响因子：
4.8
通讯作者：
Chiles, Thomas C.
中科院分区：
文献类型：
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作者：
Dufort, Fay J.;Gumina, Maria R.;Chiles, Thomas C.
背景：B淋巴细胞分化的代谢要求知之甚少。结果：分化过程中伴随着ATP-柠檬酸裂解酶（ACLY）介导的葡萄糖代谢为脂肪酸和胆固醇的合成。结论：ACLY依赖性脂肪生成是定义浆细胞分化的几种表型变化所必需的。重要性：本研究提出ACLY偶联的葡萄糖依赖性新生脂肪生成在LPS诱导的B淋巴细胞分化中的关键作用，细菌衍生的脂多糖（LPS）刺激幼稚B淋巴细胞分化为分泌免疫球蛋白（IG）的浆细胞。B淋巴细胞分化的特征在于增殖期，随后是细胞内膜分泌网络的扩张以支持IG产生。淋巴细胞生物学中的一个关键问题是幼稚B细胞如何重编程代谢以支持内膜网络响应LPS而增殖和扩张所必需的从头脂肪生成。我们报告，细胞外获得的葡萄糖代谢，部分，以支持新生脂肪生成响应LPS刺激脾B淋巴细胞。LPS刺激导致内源性ATP-柠檬酸裂解酶（ACLY）水平增加，并且这伴随着ACLY酶活性增加。ACLY从来源于尿液的柠檬酸盐产生细胞溶质乙酰辅酶A。用选择性抑制剂2-羟基-N-芳基苯磺酰胺（化合物-9; C-9）抑制LPS刺激的B细胞中的ACLY活性可阻断葡萄糖掺入从头脂质生物合成，包括胆固醇、游离脂肪酸以及中性和酸性磷脂。此外，脾B细胞中ACLY活性的抑制导致增殖的抑制和内膜扩张的缺陷，以及血浆样B细胞分化的标志物CD 138和Blimp-1的表达降低。CH 12 B淋巴瘤细胞中LPS诱导的IgM产生也需要ACLY活性。这些数据表明，ACLY介导葡萄糖依赖性从头脂肪生成响应LPS信号，并确定了ACLY在几个表型变化，定义浆细胞分化的作用。
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.