scholarly journals Novel Fatty Acid Oxidation Inhibitor Avocatinb Induces AMPK-Dependent Apoptosis of AML Cells Co-Cultured with BM-Adipocytes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3947-3947
Author(s):  
Yoko Tabe ◽  
Kazumasa Sekihara ◽  
Kaori Saitoh ◽  
Vivian Ruvolo ◽  
Takashi Miida ◽  
...  
Keyword(s):  
Cell Death ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Research Funding ◽  
Molecular Mechanisms ◽  
Culture Conditions ◽  
Acid Oxidation ◽  
Mtor Inhibition ◽  
Ros Accumulation ◽  
Apoptotic Effects

Abstract Adipocytes are the prevalent stromal cell type in adult bone marrow (BM), comprising approximately 60% of BM space in a 65-year old person. In BM environment, leukemia cells continuously adapt to deficient supply of nutrients and oxygen, acquiring quiescent and chemoresistant profiles. Fatty acid metabolism is one of the key energy pathways for AML survival (Samudio, J Clin Invest. 2010), and we previously demonstrated that AML cells activate oxidative phosphorylation and fatty acid oxidation (FAO) in the presence of BM-adipocytes (Tabe ASH 2015). These findings indicate the importance of FAO for AML cells survival under the adipocyte-abundant BM-microenvironment. A novel FAO inhibitor avocatinB, an odd-numbered carbon lipid derived from avocado fruit, has been recently shown to induce apoptosis and cell growth inhibition in AML cells (Lee, Cancer Res. 2015). In the present study, we investigated the molecular mechanisms of anti-leukemic effect of avocatinB in AML cells, utilizing THP1, OCI-AML3 and U937 AML cell lines co-cultured with human mesenchymal stem cells (MSC)-derived BM-adipocytes, mimicking the aging BM microenvironment. Treatment with avocatin B significantly induced ROS accumulation in U937 cells co-cultured with BM-adipocytes (MFI of ROS-sensitive dye; avocatinB (-) / (+); 164±50 / 581±85, p=0.04), whereas only minimum increase of ROS was observed in the absence of BM-adipocyte, indicating that avocatinB causes progressive oxidative damage in AML cells under the BM-adipocyte co-culture conditions. Of importance, avocatinB synergistically enhanced apoptotic effects of AraC in the presence of BM-adipocytes (combination index CI; adipocyte (-) / (+); THP1: 1.2 / 0.4, OCI-AML3: 0.7 / 0.3). Immunoblot analysis demonstrated that avocatinB activated the stress response kinase AMPK in THP1 and OCI-AML3 cells under BM-adipocyte co-culture conditions. AMPK is a crucial cellular energy sensor that regulates energy metabolism including FAO and gene transcription through mTOR inhibition. We therefore investigated the role of AMPK in avocatinB induced anti-leukemic effects on AML cells, utilizing AMPK knockdown (shAMPK) OCI-AML3 cells. shAMPK OCI-AML3 cells were significantly less sensitive to nutrient starvation-induced cell death in the absence of BM-adipocyte (p<0.01). While co-culture with BM-adipocytes protected control (nsAMPK) OCI-AML3 cells from spontaneous cell death, co-culture facilitated cell death of shAMPK cells. In turn, shAMPK OCI-AML cells were less sensitive to avocatinB compared to nsAMPKcells in the absence of BM-adipocyte with no additive/synergistic anti-proliferative effects of avocainB and AraC combination irrespective of the presence of BM-adipocytes (CI > 1.0). In nsAMPK cells, but not in shAMPKcells BM-adipocyte co-culture upregulated p-4EBP1 and cMyc expression which was abrogated by avocatinB and AraC combination treatment accompanied by induction of cleaved caspase 3. In summary, FAO inhibitor avocatinB induces pro-apoptotic effects through AMPK-dependent inhibition of mTOR signaling that disrupts energy homeostasis and induces ROS accumulation in AML cells under BM-adipocyte co-culture conditions. The ability of avocatinB to selectively enhance anti-leukemic effects of AraC in the presence of BM-adipocytes suggests that the strategies targeting FAO warrant further exploration in elderly AML patients. Disclosures Konopleva: Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals Human primary astrocytes increase basal fatty acid oxidation following recurrent low glucose to maintain intracellular nucleotide levels

2018 ◽  
Author(s):  
Paul G Weightman Potter ◽  
Julia M. Vlachaki Walker ◽  
Josephine L Robb ◽  
John K. Chilton ◽  
Ritchie Williamson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Molecular Mechanisms ◽  
Coupling Efficiency ◽  
Acid Oxidation ◽  
Major Barrier ◽  
Specificity And Sensitivity ◽  
Low Glucose ◽  
Primary Astrocytes

ABSTRACTHypoglycemia is a major barrier to good glucose control in type 1 diabetes and frequent exposure to hypoglycemia can impair awareness to subsequent bouts of hypoglycemia. The neural changes that occur to reduce a person’s awareness of hypoglycemia are poorly defined. Moreover, the molecular mechanisms by which glial cells contribute to hypoglycemia sensing and glucose counterregulation require further investigation. To test whether glia, specifically astrocytes, could detect changes in glucose, we utilized human primary astrocytes (HPA) and U373 astrocytoma cells and exposed them to recurrent low glucose (RLG) in vitro. This allowed measurement, with high specificity and sensitivity, of changes in cellular metabolism following RLG. We report that the AMP-activated protein kinase (AMPK) is activated over a pathophysiologically-relevant glucose concentration range. We observed an increased dependency on fatty acid oxidation for basal mitochondrial metabolism and hallmarks of mitochondrial stress including increased proton leak and reduced coupling efficiency. Relative to glucose availability, lactate release increased during low glucose but this was not modified by RLG, nor were glucose uptake or glycogen levels. Taken together, these data indicate that astrocyte mitochondria are dysfunctional following recurrent low glucose exposure, which could have implications for hypoglycemia glucose counterregulation and/or hypoglycemia awareness.

scholarly journals Inhibition of carnitine palmitoyl transferase 1A-induced fatty acid oxidation suppresses cell progression in gastric cancer

2020 ◽  
Author(s):  
Liqiang Wang ◽  
Changfeng Li ◽  
Yumei Song ◽  
ZhenKun Yan
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Molecular Mechanisms ◽  
High Rate ◽  
Acid Oxidation ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: Gastric cancer (GC) has a high rate of metastasis which thereason leading to death. Carnitine palmitoyltransferase 1a (CPT1A) has been reported to play a critical obstacle to various types of cancer progression, which is an attractive focus in anti-cancer therapy. However, the underlying molecular mechanisms of CPT1A involved in GC have not been clarified unclear. Methods: To determine the expression of CPT1A in human GC tissues and cells and illustrate whether it is correlated with the clinical pathologic characteristics and prognosis in GC patients. Its roles and potential mechanisms in regulating tumor growth and invasion were evaluated by CPT1A knockdown/overexpression of GC cells in vitro . Results: Marked upregulation of CPT1A protein expression was observed in GC cells and tissues, which was associated with grade, pathological stage, lymph node metastasis and poor prognosis in patients with GC. CPT1A overexpression also promoted the proliferation, invasion, EMT process of GC cells. In addition, CPT1A upregulation activated GC cell FAO via increasing NADP + /NADPH ratio, whereas inhibiting of FAO abolished the effects of CPT1A on GC cell proliferation and migration. Conclusion: Our results examine that CPT1A-mediated FAO activation increases GC cell proliferation and migration, supporting that CPT1A is a useful prognostic biomarker and an attractive focus for GC. Keywords: CPT1A; gastric cancer; fatty acid oxidation; prognostic; progression

scholarly journals Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Sameera Nallanthighal ◽  
Miran Rada ◽  
James Patrick Heiserman ◽  
Jennifer Cha ◽  
Jessica Sage ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Acid Oxidation

scholarly journals Arid1a protects against hepatic steatosis and insulin resistance via PPARα-mediated fatty acid oxidation

2019 ◽  
Author(s):  
Yu-Lan Qu ◽  
Chuan-Huai Deng ◽  
Qing Luo ◽  
Xue-Ying Shang ◽  
Jiao-Xiang Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Lifestyle Changes ◽  
Health Concern ◽  
Acid Oxidation ◽  
Alcoholic Fatty Liver

AbstractNon-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) have become a worldwide health concern because of lifestyle changes, but it is still lack of specific therapeutic strategies as the underlying molecular mechanisms remain poorly understood. Our previous study indicated that deficiency of Arid1a, a key component of SWI/SNF chromatin remodeling complex, initiated mouse steatohepatitis, implying that Arid1a might be essentially required for the integrity of hepatic lipid metabolism. However, the exact mechanisms of the pathological process due to Arid1a loss are unclear. In the present work, we show that hepatocyte-specific deletion of Arid1a significantly increases susceptibility to develop hepatic steatosis and insulin resistance in mice fed with high-fat diet (HFD), along with the aggravated inflammatory responses marked by increment of serum alanine amino transferase (AST), aspartate amino transferase (AST) and TNFα. Mechanistically, Arid1a deficiency leads to the reduction of chromatin modification characteristic of transcriptional activation on multiple metabolic genes, especially Cpt1a and Acox1, two rate-limiting enzyme genes for fatty acid oxidation. Furthermore, our data indicated that Arid1a loss promotes hepatic steatosis by downregulating PPARα, thereby impairing fatty acid oxidation which leads to lipid accumulation and insulin resistance. These findings reveal that targeting ARID1a might be a promising therapeutic strategy for NAFLD, NASH and insulin resistance.

scholarly journals A Comprehensive Proteome and Acetyl-Proteome Atlas Reveals Molecular Mechanisms Adapting to the Physiological Changes From Pre-laying to Peak-Laying Stage in Liver of Hens (Gallus gallus)

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhang Wang ◽  
Dandan Wang ◽  
Keren Jiang ◽  
Yulong Guo ◽  
Zhuanjian Li ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Energy Demand ◽  
Molecular Mechanisms ◽  
Laying Hens ◽  
Protein Biosynthesis ◽  
Egg Laying ◽  
Acid Oxidation ◽  
Physiological Changes ◽  
Pyruvate Metabolism

Along with sexual maturity, the liver undergoes numerous metabolic processes to adapt the physiological changes associated with egg-laying in hens. However, mechanisms regulating the processes were unclear. In this study, comparative hepatic proteome and acetyl-proteome between pre- and peak-laying hens were performed. The results showed that the upregulated proteins were mainly related to lipid and protein biosynthesis, while the downregulated proteins were mainly involved in pyruvate metabolism and were capable of inhibiting gluconeogenesis and lactate synthesis in peak-laying hens compared with that in pre-laying hens. With unchanged expression level, the significant acetylated proteins were largely functioned on activation of polyunsaturated fatty acid oxidation in peroxisome, while the significant deacetylated proteins were principally used to elevate medium and short fatty acid oxidation in mitochondria and oxidative phosphorylation. Most of the proteins which involved in gluconeogenesis, lipid transport, and detoxification were influenced by both protein expression and acetylation. Taken overall, a novel mechanism wherein an alternate source of acetyl coenzyme A was produced by activation of FA oxidation and pyruvate metabolism to meet the increased energy demand and lipid synthesis in liver of laying hens was uncovered. This study provides new insights into molecular mechanism of adaptation to physiological changes in liver of laying hens.

CD28 Regulates Metabolism In Multiple Myeloma For Cell Survival and Proliferation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5400-5400
Author(s):  
Adam T Utley ◽  
Megan Murray ◽  
Louise M Carlson ◽  
Matthew R. Farren ◽  
Jayakumar R Nair ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cell Death ◽  
Fatty Acid ◽  
T Cell ◽  
Cell Survival ◽  
Fatty Acid Oxidation ◽  
Myeloma Cell ◽  
Acid Oxidation ◽  
Myeloma Cells

Abstract Multiple myeloma is an incurable hematological malignancy of transformed plasma cells. Many cellular interactions and soluble factors have been demonstrated to play a role in myeloma pathogenesis; however, novel targets to enhance therapeutic intervention are needed. We have demonstrated that CD28 signaling in myeloma cells supports their survival during chemotherapeutic challenge in vitro and in vivo. However, the cellular mechanisms by which CD28 confers this survival advantage to myeloma cells are not completely understood. CD28 is best characterized as the canonical T cell co-stimulatory molecule. During T cell activation, CD28 signaling induces glycolysis, a metabolic program required for T cell proliferation and functional maturation. In the absence of glycolysis, T cells utilize fatty acid oxidation for energy production through the mitochondria. However, the way in which CD28 regulates metabolism in multiple myeloma is not well understood. Here we present evidence that CD28 signaling induces glut1 expression, and that poisoning the glycolytic pathway inhibits proliferation and survival of myeloma cells. AMPK, an energy sensitive kinase known to regulate metabolism by driving fatty acid oxidation, is normally activated when cellular energy levels are low. Interestingly, poisoning glycolysis with a glucose analogue that cannot be processed (2DG) leads to AMPK inhibition in myeloma cells. Furthermore, pharmacological activation of AMPK by AICAR, an AMP analogue, is not sufficient to rescue myeloma cell proliferation from glycolytic inhibition and in fact increases cell death (p<.01 from no treatment, p<.05 from 2DG). This evidence suggests that multiple myeloma cells are absolutely dependent upon CD28-mediated glycolysis for proliferation and survival, and that myeloma cells cannot utilize fatty acid oxidation as a subsidiary metabolic pathway for proliferation in the absence of glycolysis. This understanding will allow us to target metabolism in multiple myeloma as a novel therapeutic strategy through pharmacological targeting of the CD28 pathway. This approach can be quickly translated into the clinic, as there are FDA approved drugs which activate AMPK (Metformin) and block CD28 signaling (Abatacept). Disclosures: Off Label Use: Abatacept, purpose to prevent CD28-mediated cell survival in multiple myeloma Metformin, purpose to activate AMPK in driving multiple myeloma cell death.

scholarly journals BMPR2 promotes fatty acid oxidation and protects white adipocytes from cell death in mice

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Shuwen Qian ◽  
Jiabao Pan ◽  
Yan Su ◽  
Yan Tang ◽  
Yina Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
White Adipocytes

scholarly journals Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications

2018 ◽  
Vol 46 (3) ◽  
pp. 599-607 ◽  
Author(s):  
Andrew J. Murray ◽  
Hugh E. Montgomery ◽  
Martin Feelisch ◽  
Michael P.W. Grocott ◽  
Daniel S. Martin
Keyword(s):  
Fatty Acid ◽  
High Altitude ◽  
Fatty Acid Oxidation ◽  
Oxygen Delivery ◽  
Molecular Mechanisms ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxygen Utilisation ◽  
Hif Pathway

Ascent to high altitude is associated with physiological responses that counter the stress of hypobaric hypoxia by increasing oxygen delivery and by altering tissue oxygen utilisation via metabolic modulation. At the cellular level, the transcriptional response to hypoxia is mediated by the hypoxia-inducible factor (HIF) pathway and results in promotion of glycolytic capacity and suppression of oxidative metabolism. In Tibetan highlanders, gene variants encoding components of the HIF pathway have undergone selection and are associated with adaptive phenotypic changes, including suppression of erythropoiesis and increased blood lactate levels. In some highland populations, there has also been a selection of variants in PPARA, encoding peroxisome proliferator-activated receptor alpha (PPARα), a transcriptional regulator of fatty acid metabolism. In one such population, the Sherpas, lower muscle PPARA expression is associated with a decreased capacity for fatty acid oxidation, potentially improving the efficiency of oxygen utilisation. In lowlanders ascending to altitude, a similar suppression of fatty acid oxidation occurs, although the underlying molecular mechanism appears to differ along with the consequences. Unlike lowlanders, Sherpas appear to be protected against oxidative stress and the accumulation of intramuscular lipid intermediates at altitude. Moreover, Sherpas are able to defend muscle ATP and phosphocreatine levels in the face of decreased oxygen delivery, possibly due to suppression of ATP demand pathways. The molecular mechanisms allowing Sherpas to successfully live, work and reproduce at altitude may hold the key to novel therapeutic strategies for the treatment of diseases to which hypoxia is a fundamental contributor.

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