LKB1 induces apical trafficking of Silnoon, a monocarboxylate transporter, in <i>Drosophila melanogaster</i>

Jang, Cholsoon,Lee, Gina,Chung, Jongkyeong The Rockefeller University Press 2008 The Journal of cell biology Vol.183 No.1

<P>Silnoon (Sln) is a monocarboxylate transporter (MCT) that mediates active transport of metabolic monocarboxylates such as butyrate and lactate. Here, we identify Sln as a novel LKB1-interacting protein using <I>Drosophila melanogaster</I> genetic modifier screening. Sln expression does not affect cell cycle progression or cell size but specifically enhances LKB1-dependent apoptosis and tissue size reduction. Conversely, down-regulation of Sln suppresses LKB1-dependent apoptosis, implicating Sln as a downstream mediator of LKB1. The kinase activity of LKB1 induces apical trafficking of Sln in polarized cells, and LKB1-dependent Sln trafficking is crucial for triggering apoptosis induced by extracellular butyrate. Given that LKB1 functions to control both epithelial polarity and cell death, we propose Sln is an important downstream target of LKB1.</P>

Angiopoietin-2 Exocytosis Is Stimulated by Sphingosine-1-Phosphate in Human Blood and Lymphatic Endothelial Cells

Jang, Cholsoon,Koh, Young Jun,Lim, Nam Kyu,Kang, Hyun Jung,Kim, Duk Hoon,Park, Sung Kwang,Lee, Gyun Min,Jeon, Choon Ju,Koh, Gou Young Ovid Technologies Wolters Kluwer -American Heart A 2009 Arteriosclerosis, thrombosis, and vascular biology Vol.29 No.3

<P>OBJECTIVE: Although diverse functions of angiopoietin-2 (Ang2) have been revealed, little is known about upstream signaling molecules regulating Ang2 exocytosis. We therefore investigated the mechanism of Ang2 exocytosis in human blood and lymphatic endothelial cells (BECs and LECs) by stimulation with sphingosine-1-phosphate (S1P). METHODS AND RESULTS: By immunostaining and ELISA analyses using our newly developed human Ang2-specific antibodies, Ang2 exocytosis from human endothelial cells was examined. Both exogenous and endogenous S1P trigger rapid Ang2 exocytosis in time- and dose-dependent manners. Intriguingly, S1P-induced Ang2 exocytosis is higher in LECs than BECs. These effects of S1P are mainly mediated by the endothelial differentiation gene receptor 1, which subsequently activates its downstream phospholipase C and intracellular calcium mobilization to trigger Ang2 exocytosis. Consistently, S1P also dramatically stimulates Ang2 exocytosis from the ECs of ex vivo-incubated blood vessels. CONCLUSION: These results imply that the rapid secretion of Ang2 by exocytosis from endothelial cells is another possible mechanism underlying S1P-induced angiogenesis and inflammation.</P>

Profound but Dysfunctional Lymphangiogenesis via Vascular Endothelial Growth Factor Ligands from CD11b⁺ Macrophages in Advanced Ovarian Cancer

Jeon, Bong-Hyun,Jang, Cholsoon,Han, Jinah,Kataru, Raghu P.,Piao, Lianhua,Jung, Keehoon,Cha, Hye Ji,Schwendener, Reto A.,Jang, Kyu Yun,Kim, Kwan-Sik,Alitalo, Kari,Koh, Gou Young American Association for Cancer Research 2008 Cancer Research Vol.68 No.4

<P>Severe ascites is a hallmark of advanced ovarian cancer (OVCA), yet the underlying mechanism that creates an imbalance between peritoneal vascular leakage and lymphatic drainage is unknown. Here, we identified and characterized peritoneal lymphatic vessels in OVCA mice, a model generated by implantation of human OVCA cells into athymic nude mice. The OVCA mice displayed substantial lymphangiogenesis and lymphatic remodeling, massive infiltration of CD11b(+)/LYVE-1(+) macrophages and disseminated carcinomatosis in the mesentery and diaphragm, and progressive chylous ascites formation. Functional assays indicated that the abnormally abundant lymphatic vessels in the diaphragm were not conductive in peritoneal fluid drainage. Moreover, lipid absorbed from the gut leaked out from the aberrant mesenteric lymphatic vessels. Our results indicate that vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF-A from CD11b(+) macrophages are responsible for producing OVCA-induced dysfunctional lymphangiogenesis, although other cell types contribute to the increased ascites formation. Accordingly, the combined blockade of VEGF-C/D and VEGF-A signaling with soluble VEGF receptor-3 and VEGF-Trap, respectively, markedly inhibited chylous ascites formation. These findings provide additional therapeutic targets to ameliorate chylous ascites formation in patients with advanced OVCA.</P>

Metabolic flux between organs measured by arteriovenous metabolite gradients

Bae Hosung,Lam Katie,Jang Cholsoon 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Mammalian organs convert dietary nutrients into circulating metabolites and share them to maintain whole-body metabolic homeostasis. While the concentrations of circulating metabolites have been frequently measured in a variety of pathophysiological conditions, the exchange flux of circulating metabolites between organs is not easily measurable due to technical difficulties. Isotope tracing is useful for measuring such fluxes for a metabolite of interest, but the shuffling of isotopic atoms between metabolites requires mathematical modeling. Arteriovenous metabolite gradient measurements can complement isotope tracing to infer organ-specific net fluxes of many metabolites simultaneously. Here, we review the historical development of arteriovenous measurements and discuss their advantages and limitations with key example studies that have revealed metabolite exchange flux between organs in diverse pathophysiological contexts.

Metabolism and Health Impacts of Dietary Sugars

Alam Yasmine Henna,Kim Raymond,Jang Cholsoon 한국지질동맥경화학회 2022 지질·동맥경화학회지 Vol.11 No.1

Consumption of excessive amounts of added sugars and their effects on human health has been a major concern in the last several decades. Epidemiological data suggest that the incidence of metabolic disorders, such as obesity, nonalcoholic fatty liver disease, cardiovascular disease and diabetes, has increased due to chronic surplus consumption of these sugars. While many of these sugars have been isolated and studied for centuries, their health impacts and exact underlying mechanisms are still unclear. In this review, we discuss the pathophysiological role of 6 major simple sugars present in the human diet and the biochemical and molecular pathways related to their metabolism by different organs and gut microbiota, with a focus on the most recent investigations.

The interaction between the gut microbiota and dietary carbohydrates in nonalcoholic fatty liver disease

Park Grace,Jung Sunhee,Wellen Kathryn E.,Jang Cholsoon 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-

Imbalance between fat production and consumption causes various metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), one such pathology, is characterized by abnormally increased fat synthesis and subsequent fat accumulation in hepatocytes 1,2 . While often comorbid with obesity and insulin resistance, this disease can also be found in lean individuals, suggesting specific metabolic dysfunction 2 . NAFLD has become one of the most prevalent liver diseases in adults worldwide, but its incidence in both children and adolescents has also markedly increased in developed nations 3,4 . Progression of this disease into nonalcoholic steatohepatitis (NASH), cirrhosis, liver failure, and hepatocellular carcinoma in combination with its widespread incidence thus makes NAFLD and its related pathologies a significant public health concern. Here, we review our understanding of the roles of dietary carbohydrates (glucose, fructose, and fibers) and the gut microbiota, which provides essential carbon sources for hepatic fat synthesis during the development of NAFLD.

Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation

Lee, Choong-kun,Jeong, Seung-hwan,Jang, Cholsoon,Bae, Hosung,Kim, Yoo Hyung,Park, Intae,Kim, Sang Kyum,Koh, Gou Young American Association for the Advancement of Scienc 2019 Science Vol.363 No.6427

<P><B>Fueling lymph node metastases</B></P><P>Metastatic cells can migrate from a primary tumor to distant organs through two routes: They can enter the bloodstream directly, or they can enter a lymph node adjacent to the primary tumor. Little is known about the biological mechanisms that allow tumor cells to survive and grow within lymph nodes. Studying mouse models, Lee <I>et al.</I> found that tumor cells adapt to the lymph node microenvironment by shifting their metabolism toward fatty acid oxidation. This occurs through activation of a signaling pathway driven by the yes-associated protein (YAP) transcription factor. Importantly, inhibition of fatty acid oxidation or YAP signaling suppressed lymph node metastasis in the mice.</P><P><I>Science</I>, this issue p. 644</P><P>In cancer patients, metastasis of tumors to sentinel lymph nodes (LNs) predicts disease progression and often guides treatment decisions. The mechanisms underlying tumor LN metastasis are poorly understood. By using comparative transcriptomics and metabolomics analyses of primary and LN-metastatic tumors in mice, we found that LN metastasis requires that tumor cells undergo a metabolic shift toward fatty acid oxidation (FAO). Transcriptional coactivator yes-associated protein (YAP) is selectively activated in LN-metastatic tumors, leading to the up-regulation of genes in the FAO signaling pathway. Pharmacological inhibition of FAO or genetic ablation of YAP suppressed LN metastasis in mice. Several bioactive bile acids accumulated to high levels in the metastatic LNs, and these bile acids activated YAP in tumor cells, likely through the nuclear vitamin D receptor. Inhibition of FAO or YAP may merit exploration as a potential therapeutic strategy for mitigating tumor metastasis to LNs.</P>

T Lymphocytes Negatively Regulate Lymph Node Lymphatic Vessel Formation

Kataru, Raghu P.,Kim, Honsoul,Jang, Cholsoon,Choi, Dong Kyu,Koh, Bong Ihn,Kim, Minah,Gollamudi, Sudheer,Kim, Yun-Keun,Lee, Seung-Hyo,Koh, Gou Young Elsevier 2011 Immunity Vol.34 No.1

<P><B>Summary</B></P><P>Lymph node lymphatic vessels (LNLVs) serve as a conduit to drain antigens from peripheral tissues to within the lymph nodes. LNLV density is known to be positively regulated by vascular endothelial growth factors secreted by B cells, macrophages, and dendritic cells (DCs). Here, we show that LNLV formation was negatively regulated by T cells. In both steady and inflammatory states, the density of LNLVs was increased in the absence of T cells but decreased when T cells were restored. Interferon-γ secretion by T cells suppressed lymphatic-specific genes in lymphatic endothelial cells and consequently caused marked reduction in LNLV formation. When T cells were depleted, recruitment of antigen-carrying DCs to LNs was augmented, reflecting a compensatory mechanism for antigen presentation to T cells through increased LNLVs. Thus, T cells maintain the homeostatic balance of LNLV density through a negative paracrine action of interferon-γ.</P> <P><B>Graphical Abstract</B></P><P><ce:figure id='dfig1'></ce:figure></P><P><B>Highlights</B></P><P>► Lymphatic vessels (LVs) are absent in the T cell zone of lymph nodes (LNs) ► T cells reduce LNLV density by secreting IFN-<B>γ</B> ► IFN-<B>γ</B> downregulates lymphatic-specific genes ► IFN-<B>γ</B> prevents lymphangiogenesis</P>

Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution

Kataru, Raghu P.,Jung, Keehoon,Jang, Cholsoon,Yang, Hanseul,Schwendener, Reto A.,Baik, Jung Eun,Han, Seung Hyun,Alitalo, Kari,Koh, Gou Young American Society of Hematology 2009 Blood Vol.113 No.22

<P>Using a bacterial pathogen-induced acute inflammation model in the skin, we defined the roles of local lymphatic vessels and draining lymph nodes (DLNs) in antigen clearance and inflammation resolution. At the peak day of inflammation, robust expansion of lymphatic vessels and profound infiltration of CD11b+/Gr-1+ macrophages into the inflamed skin and DLN were observed. Moreover, lymph flow and inflammatory cell migration from the inflamed skin to DLNs were enhanced. Concomitantly, the expression of lymphangiogenic growth factors such as vascular endothelial growth factor C (VEGF-C), VEGF-D, and VEGF-A were significantly up-regulated in the inflamed skin, DLNs, and particularly in enriched CD11b+ macrophages from the DLNs. Depletion of macrophages, or blockade of VEGF-C/D or VEGF-A, largely attenuated these phenomena, and produced notably delayed antigen clearance and inflammation resolution. Conversely, keratin 14 (K14)-VEGF-C transgenic mice, which have dense and enlarged lymphatic vessels in the skin dermis, exhibited accelerated migration of inflammatory cells from the inflamed skin to the DLNs and faster antigen clearance and inflammation resolution. Taken together, these results indicate that VEGF-C, -D, and -A derived from the CD11b+/Gr-1+ macrophages and local inflamed tissues play a critical role in promoting antigen clearance and inflammation resolution.</P>

Membrane proteomic analysis of human mesenchymal stromal cells during adipogenesis

Jeong, Ju Ah,Ko, Kyung-Min,Park, Hyung Soon,Lee, Jinsook,Jang, Cholsoon,Jeon, Choon-Ju,Koh, Gou Young,Kim, Hoeon WILEY-VCH 2007 Proteomics Vol. No.

<P>Mesenchymal stromal cells (MSCs) have proven useful for cell and immune therapy, but the molecular constituents responsible for their functionalities, in particular, those on the plasma membrane, remain largely unknown. Here we employed both gel and nongel based MS to analyze human MSCs' membrane proteome before and after adipogenesis. 2-DE of cells that were pretreated with membrane impermeable fluorescent dyes revealed that both the whole cell proteome and the cell surface subproteome were independent of donors. LC coupled with tandem MS analysis of the plasma membrane-containing fraction allowed us to identify 707 proteins, approximately half of which could be annotated as membrane-related proteins. Of particular interest was a subset of ectodomain-containing membrane-bound proteins that encompass most known surface markers for MSCs, but also contain a multitude of solute carriers and ATPases. Upon adipogenic differentiation, this proteomic profile was amended to include several proteins involved in lipid metabolism and trafficking, at the expense of, most noticeably, ectoenzymes. Our results here provide not only a basis for future studies of MSC-specific molecular mechanisms, but also a molecular inventory for the development of antibody-based cell isolation and identification procedures.</P>