Pann-Ghill Suh

Lipids are crucial components of cellular function owing to their role in membrane formation, intercellular signaling, energy storage, and homeostasis maintenance. In the brain, lipid dysregulations have been associated with the etiology and progression of neurodegeneration and other neurological pathologies. Hence, brain lipids are emerging as important potential targets for the early diagnosis and prognosis of neurological diseases. This review aims to highlight the significance and usefulness of lipidomics in diagnosing and treating brain diseases. We explored lipid alterations associated with brain diseases, paying attention to organ-specific characteristics and the functions of brain lipids. As the recent advances in brain lipidomics would have been impossible without advances in analytical techniques, we provide up-to-date information on mass spectrometric approaches and integrative analysis with other omic approaches. Last, we present the potential applications of lipidomics combined with artificial intelligence techniques and interdisciplinary collaborative research for treating brain diseases with clinical heterogeneities.

Breast cancer progression results from subversion of multiple intra- or intercellular signaling pathways in normal mammary tissues and their microenvironment, which have an impact on cell differentiation, proliferation, migration, and angiogenesis. Phospholipases (PLC, PLD and PLA) are essential mediators of intra- and intercellular signaling. They hydrolyze phospholipids, which are major components of cell membrane that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid, and arachidonic acid. Enzymatic processing of phospholipids by phospholipases converts these molecules into lipid mediators that regulate multiple cellular processes, which in turn can promote breast cancer progression. Thus, dysregulation of phospholipases contributes to a number of human diseases, including cancer. This review describes how phospholipases regulate multiple cancer-associated cellular processes, and the interplay among different phospholipases in breast cancer. A thorough understanding of the breast cancer–associated signaling networks of phospholipases is necessary to determine whether these enzymes are potential targets for innovative therapeutic strategies.

Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4+ and CD8+ T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8+ T cells is qualitatively different from that in CD4+ T cells, since CD8α ignites another cardinal signaling cascade involving phospholipase C β4 (PLCβ4). TCR-mediated responses were severely impaired in PLCβ4-deficient CD8+ T cells, whereas those in CD4+ T cells were intact. PLCβ4-deficient CD8+ T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP3 generation. Binding of PLCβ4 to the cytoplasmic tail of CD8α was important for CD8+ T cell activation. Furthermore, GNAQ interacted with PLCβ4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLCβ4, and activated CD8+ T cells in a PLCβ4-dependent fashion. PLCβ4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLCβ4 differentiates TCR signaling in CD4+ and CD8+ T cells and selectively promotes CD8+ T cell–dependent adaptive immunity.

Dysregulation of the adipo‐osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator‐activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone‐induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high‐fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

Differentiation and proliferation of keratinocyte is controlled by various signaling pathways. The epidermal growth factor receptor (EGFR) is known to be an important regulator of multiple epidermal functions. Inhibition of EGFR signaling disturbs keratinocyte proliferation, differentiation, and migration. Previous studies have revealed that one of the EGFR downstream signaling molecules, phospholipase Cγ1 (PLCγ1), regulates differentiation, proliferation, and migration of keratinocytes in in vitro cell culture system. However, the role of PLCγ1 in the regulation of keratinocyte functions in animal epidermis remains unexplored. In this study, we generated keratinocyte‐specific PLCγ1 knockout (KO) mice (PLCγ1 cKO mice). Contrary to our expectations, loss of PLCγ1 did not affect differentiation, proliferation, and migration of interfollicular keratinocytes. We further examined the role of PLCγ1 in irritant contact dermatitis (ICD), in which epidermal cells play a pivotal role. Upon irritant stimulation, PLCγ1 cKO mice showed exaggerated ICD responses. Further study revealed that epidermal loss of PLCγ1 induced sebaceous gland hyperplasia, indicating that PLCγ1 regulates homeostasis of one of the epidermal appendages. Taken together, our results indicate that, although PLCγ1 is dispensable in interfollicular keratinocyte for normal differentiation, proliferation, and migration, it is required for normal ICD responses. Our results also indicate that PLCγ1 regulates homeostasis of sebaceous glands.

PLC‐β exerts biologic influences through GPCR. GPCRs are involved in regulating glucose‐stimulated insulin secretion (GSIS). Previous studies have suggested that PLC‐βs might play an important role in pancreatic β cells. However, because of a lack of the specific inhibitors of PLC‐β isozymes and appropriate genetic models, the in vivo function of specific PLC‐β isozymes in pancreatic β cells and their physiologic relevance in the regulation of insulin secretion have not been studied so far. The present study showed that PLC‐β1 was crucial for β‐cell function by generation of each PLC‐β conditional knockout mouse. Mice lacking PLC‐β1 in β cells exhibited a marked defect in GSIS, leading to glucose intolerance. In ex vivo studies, the secreted insulin level and Ca ²⁺ response in Plcb1 ^f/f ; pancreas/duodenum homeobox protein 1 ( Pdx1 )‐Cre recombinase‐estrogen receptor T2 ( CreERt2 ) islets was lower than those in the Plcb1 ^f/f islets under the high‐glucose condition. PLC‐β1 led to potentiate insulin secretion via stimulation of particular G _q ‐protein–coupled receptors. Plcb1 ^f/f ; Pdx1‐CreERt2 mice fed a high‐fat diet developed more severe glucose intolerance because of a defect in insulin secretion. The present study identified PLC‐β1 as an important molecule that regulates β cell insulin secretion and can be considered a candidate for therapeutic intervention in diabetes mellitus.—Hwang, H.‐J., Yang, Y. R., Kim, H. Y., Choi, Y., Park, K.‐S., Lee, H., Ma, J. S., Yamamoto, M., Kim, J., Chae, Y. C., Choi, J. H., Coceo, L., Berggren, P.‐O., Jang, H.‐J., Suh, P.‐G. Phospholipase Cβ1 potentiates glucose‐stimulated insulin secretion. FASEB J. 33, 10668–10679 (2019). www.fasebj.org

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