Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism.

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T cell metabolism drives immunity

What determines whether a developing thymocyte becomes a CD4+ or CD8+ T cell has been an issue of longstanding debate. Here, the authors review the models that have been proposed to explain CD4/CD8-lineage choice and update us on the environmental and transcription factors that might mediate this decision.

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Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice.

Lysophosphatidylcholine (LPC) is increasingly recognized as a key marker/factor positively associated with cardiovascular and neurodegenerative diseases. However, findings from recent clinical lipidomic studies of LPC have been controversial. A key issue is the complexity of the enzymatic cascade involved in LPC metabolism. Here, we address the coordination of these enzymes and the derangement that may disrupt LPC homeostasis, leading to metabolic disorders. LPC is mainly derived from the turnover of phosphatidylcholine (PC) in the circulation by phospholipase A2 (PLA2). In the presence of Acyl-CoA, lysophosphatidylcholine acyltransferase (LPCAT) converts LPC to PC, which rapidly gets recycled by the Lands cycle. However, overexpression or enhanced activity of PLA2 increases the LPC content in modified low-density lipoprotein (LDL) and oxidized LDL, which play significant roles in the development of atherosclerotic plaques and endothelial dysfunction. The intracellular enzyme LPCAT cannot directly remove LPC from circulation. Hydrolysis of LPC by autotaxin, an enzyme with lysophospholipase D activity, generates lysophosphatidic acid, which is highly associated with cancers. Although enzymes with lysophospholipase A1 activity could theoretically degrade LPC into harmless metabolites, they have not been found in the circulation. In conclusion, understanding enzyme kinetics and LPC metabolism may help identify novel therapeutic targets in LPC-associated diseases.

https://www.mdpi.com/1422-0067/20/5/1149/pdf

An Updated Review of Lysophosphatidylcholine Metabolism in Human Diseases.

Developmental and Molecular Characterization of Emerging β- and γδ-Selected Pre-T Cells in the Adult Mouse Thymus

Cells must duplicate their mass in order to proliferate. Glucose and glutamine are the major nutrients consumed by proliferating mammalian cells, but the extent to which these and other nutrients contribute to cell mass is unknown. We quantified the fraction of cell mass derived from different nutrients and found that the majority of carbon mass in cells is derived from other amino acids, which are consumed at much lower rates than glucose and glutamine. While glucose carbon has diverse fates, glutamine contributes most to protein, suggesting that glutamine's ability to replenish tricarboxylic acid cycle intermediates (anaplerosis) is primarily used for amino acid biosynthesis. These findings demonstrate that rates of nutrient consumption are indirectly associated with mass accumulation and suggest that high rates of glucose and glutamine consumption support rapid cell proliferation beyond providing carbon for biosynthesis.

Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells

Activation of T cells accompanies remarkable enhancement of metabolism. Sufficient and continuous nutrient supply is therefore important to support immune reaction in T cells. However, the mechanism of the promotion of nutrient incorporation in activated T cells has not been elucidated. In this study, we show that L-type amino acid transporter 1 (LAT1) is a major transporter for essential amino acids into activated human T cells. CD3/CD28 stimulation in primary human T cells triggered dramatic induction of LAT1 expression mediated by NF-κB and AP-1. Functional disturbance of LAT1 by a specific inhibitor and by small interfering RNA in human T cells suppressed essential amino acid uptake and induced a stress response mediated by DNA damage–inducible transcript 3 to attenuate cytokine production via inhibition of NF-κB and NFAT activities. These results uncover the previously unknown mechanism by which T cells accelerate essential amino acid uptake upon activation and adapt to essential amino acid starvation. Our results also raise the possibility for application of an LAT1 inhibitor as a new drug for therapy of disease caused by exaggerated immune response.

/pdf/lat1-is-a-critical-transporter-of-essential-amino-acids-for-nfylivppec.pdf

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

The Runx family of transcription factors is thought to regulate the differentiation of thymocytes. Runx3 protein is detected mainly in the CD4 − 8 + subset of T lymphocytes. In the thymus of Runx3 -deficient mice, CD4 expression is de-repressed and CD4 − 8 + thymocytes do not develop. This clearly implicates Runx3 in CD4 silencing, but does not necessarily prove its role in the differentiation of CD4 − 8 + thymocytes per se. In the present study, we created transgenic mice that overexpress Runx3 and analyzed the development of thymocytes in these animals. In the Runx3 -transgenic thymus, the number of CD4 − 8 + cells was greatly increased, whereas the numbers of CD4 + 8 + and CD4 + 8 − cells were reduced. The CD4 − 8 + transgenic thymocytes contained mature cells with a TCR high HSA low phenotype. These cells were released from the thymus and contributed to the elevated level of CD4 − 8 + cells relative to CD4 + 8 − cells in the spleen. Runx3 overexpression also increased the number of mature CD4 − 8 + thymocytes in mice with class II-restricted, transgenic TCR and in mice with a class I-deficient background, both of which are favorable for CD4 + 8 − lineage selection. Thus, Runx3 can drive thymocytes to select the CD4 − 8 + lineage. This activity is likely to be due to more than a simple silencing of CD4 gene expression.

Overexpression of the Runx3 transcription factor increases the proportion of mature thymocytes of the CD8 single-positive lineage.

Tumor cells take up a massive amount of nutrition compared to normal cells for increased metabolism. Therefore, special transporters for organic materials are required to satisfy the powerful consumption of nutrition in tumor cells. L-type amino acid transporter 1 (LAT1) incorporates large neutral amino acids, most of which are also categorized as essential amino acids, into cells in a Na+-independent manner. Because of its high expression levels in a variety of cancer cells, it is speculated that LAT1 functions as a key transporter for highly effective delivery of essential amino acids into cancer cells. In this regard, LAT1 inhibitor is expected to have clinical benefit for cancer therapy. However, the molecular mechanism of enrichment of LAT1 in cancer cells remains poorly understood. Here, we show that a proto-oncogene, c-Myc, is a critical positive regulator of LAT1 expression in MIA Paca-2 human pancreatic cancer cells. The uptake of leucine, a representative neutral amino acid, was strictly dependent on LAT1 in MIA Paca-2 cells, and siRNA-mediated knockdown of LAT1 inhibited cell proliferation. Diminished c-Myc expression with siRNA resulted in severe reduction of LAT1 protein levels as well as mRNA levels, which, in turn, led to a significant defect of leucine incorporation. The LAT1 promoter has a canonical c-Myc binding sequence and overexpression of c-Myc increased LAT1 promoter activity, whereas mutation of c-Myc binding site diminished this effect. Our results suggest biological significance of LAT1 in tumor growth and molecular machinery that could explain why LAT1 is preferentially expressed in cancer cells.

/pdf/c-myc-is-crucial-for-the-expression-of-lat1-in-mia-paca-2-24tw3io6ie.pdf

c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic cancer cells.

L-type amino acid transporters (LATs) mainly assist the uptake of neutral amino acids into cells. Four LATs (LAT1, LAT2, LAT3 and LAT4) have so far been identified. LAT1 (SLC7A5) has been attracting much attention in the field of cancer research since it is commonly up-regulated in various cancers. Basic research has made it increasingly clear that LAT1 plays a predominant role in malignancy. The functional significance of LAT1 in cancer and the potential therapeutic application of the features of LAT1 to cancer management are described in this review.

Novel therapeutic approaches targeting L-type amino acid transporters for cancer treatment

Unlike normal cells, cancer cells undergo unlimited growth and multiplication, causing them to require massive amounts of amino acid to support their continuous metabolism. Among the amino acid tra...

https://journals.sagepub.com/doi/pdf/10.1177/1010428317694545

Keitaro Hayashi

Papers

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Overexpression of the Runx3 transcription factor increases the proportion of mature thymocytes of the CD8 single-positive lineage.

c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic cancer cells.

Novel therapeutic approaches targeting L-type amino acid transporters for cancer treatment

Inhibition of l-type amino acid transporter 1 activity as a new therapeutic target for cholangiocarcinoma treatment: