Abstract TMP28:
            De Novo
            Fatty Acid Synthesis In Cd4
            +
            T Cells After Cerebral Ischemic Stroke - A New Target of Post-stroke Immune Modulation

The metabolic reprogramming of peripheral CD4+ T cells that occurs after stroke can lead to imbalanced differentiation of CD4+ T cells, including regulation of T cells, and presents a promising target for poststroke immunotherapy. However, the regulatory mechanism underlying the metabolic reprogramming of peripheral CD4+ T cell remains unknown. In this study, using combined transcription and metabolomics analyses, flow cytometry, and conditional knockout mice, we demonstrate that the receptor for advanced glycation end products (RAGE) can relay the ischemic signal to CD4+ T cells, which underwent acetyl coenzyme A carboxylase 1(ACC1)-dependent metabolic reprogramming after stroke. Furthermore, by administering soluble RAGE (sRAGE) after stroke, we demonstrate that neutralization of RAGE reversed the enhanced fatty acid synthesis of CD4+ T cells and the post-stroke imbalance of Treg/Th17. Finally, we found that post-stroke sRAGE treatment protected against infarct volume and ameliorated functional recovery. In conclusion, sRAGE can serve as a novel immunometabolic modulator that ameliorates ischemic stroke recovery by inhibiting fatty acid synthesis and thus favoring CD4+ T cells polarization toward Treg after cerebral ischemia injury. The above findings provide new insights for the treatment of neuroinflammatory responses after ischemia stroke.

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Synthesis of fatty acids in the perfused mouse liver

Biochemical Journal ◽

10.1042/bj1420611 ◽

1974 ◽

Vol 142 (3) ◽

pp. 611-618 ◽

Cited By ~ 57

Author(s):

D. Michael W. Salmon ◽

Neil L. Bowen ◽

Douglas A. Hems

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Saturated Fatty Acids ◽

Carbon Sources ◽

Acid Synthesis ◽

Hepatic Glycogen ◽

Total Rate ◽

Glucose Carbon

1. Fatty acid synthesis de novo was measured in the perfused liver of fed mice. 2. The total rate, measured by the incorporation into fatty acid of3H from3H2O (1–7μmol of fatty acid/h per g of fresh liver), resembled the rate found in the liver of intact mice. 3. Perfusions with l-[U-14C]lactic acid and [U-14C]glucose showed that circulating glucose at concentrations less than about 17mm was not a major carbon source for newly synthesized fatty acid, whereas lactate (10mm) markedly stimulated fatty acid synthesis, and contributed extensive carbon to lipogenesis. 4. The identification of 50% of the carbon converted into newly synthesized fatty acid lends further credibility to the use of3H2O to measure hepatic fatty acid synthesis. 5. The total rate of fatty acid synthesis, and the contribution of glucose carbon to lipogenesis, were directly proportional to the initial hepatic glycogen concentration. 6. The proportion of total newly synthesized lipid that was released into the perfusion medium was 12–16%. 7. The major products of lipogenesis were saturated fatty acids in triglyceride and phospholipid. 8. The rate of cholesterol synthesis, also measured with3H2O, expressed as acetyl residues consumed, was about one-fourth of the basal rate of fatty acid synthesis. 9. These results are discussed in terms of the carbon sources of hepatic newly synthesized fatty acids, and the effect of glucose, glycogen and lactate in stimulating lipogenesis, independently of their role as precursors.

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