scholarly journals Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice

Hepatology ◽  
2012 ◽  
Vol 55 (4) ◽  
pp. 1070-1082 ◽  
Author(s):  
Chunbin Zhang ◽  
Guohui Wang ◽  
Ze Zheng ◽  
Krishna Rao Maddipati ◽  
Xuebao Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Stress ◽  
Acid Oxidation ◽  
Hepatic Lipogenesis ◽  
Element Binding Protein ◽  
Responsive Element ◽  
Camp Responsive Element Binding

High PRMT1 Expression Promotes the Progression of Acute Megakaryocytic Leukemia Via Controlling Metabolic Pathways

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1551-1551
Author(s):  
Hairui Su ◽  
Han Guo ◽  
Ngoc-Tung Tran ◽  
Minkui Luo ◽  
Xinyang Zhao
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Pathways ◽  
Metabolic Stress ◽  
Metabolic Reprogramming ◽  
Metabolic Inhibitors ◽  
Acid Oxidation ◽  
Epigenetic Changes ◽  
Acute Megakaryocytic Leukemia ◽  
Megakaryocyte Differentiation

Abstract Metabolic reprogramming is needed not only to accommodate but also to drive leukemia progression. Yet very little is known on genetic factors other than IDH1 mutations, which can drive leukemogenesis via metabolic reprogramming. Here, we will present data to suggest that protein arginine methyltransferases 1 (PRMT1) is a driver for acute megakaryocytic leukemia via reprogramming metabolism. PRMT1 is highly expressed in megakaryocyte-erythrocyte progenitor cells and downregulated during the terminal differentiation of megakaryocytes. Constitutively high expression of PRMT1 in acute megakaryoblastic leukemia (AMKL) blocks megakaryocyte differentiation. PRMT1 upregulates RBM15 protein level via methylation-dependent ubiquitylation pathway (Zheng et al. Elife, 2015). In this presentation, we discovered that metabolic stress such as hypoxia downregulates PRMT1 protein level. Thus, metabolic stress is the upstream signal for the PRMT1-RBM15 pathway. We have identified that RBM15 specifically binds to 3'UTR of mRNAs of genes involved in metabolic pathways. Using RNA-immunoprecipitation with anti-RBM15 antibody and real-time PCR assays, we validated that RBM15 binds to mRNAs of genes involved in fatty acid oxidation and glycolysis. We transduced PRMT1 into an RBM15-MKL1 expressing cell line 6133. Overexpression of PRMT1 renders 6133 cells to grow in a cytokine-independent manner with increased mitochondria biogenesis, which in turn produces higher concentration of ATP in our metabolomic analysis. Based on the analysis of metabolomics data and RBM15-target genes, we conclude that PRMT1 promotes the usage of glucose as bioenergy via oxidative phosphorylation and inhibits fatty acid oxidation. Given that acetyl-coA is higher in PRMT1 expressing 6133 cells, we asked whether histone acetylation is upregulated in PRMT1 overexpressed 6133 cells. Indeed, we found higher histone acetylation level in PRMT1 highly expressed cells. We also found that propionylated histone is reduced, which is consistent with reduced fatty acid oxidation. Propionyl-CoA molecules are produced from fatty acids with odd carbon numbers. Thus PRMT1-mediated metabolic reprogramming changes epigenetic programming during leukemia progression. Intriguing, we also found PRMT1 overexpression enhances histone H3S10 phosphorylation via methylation-dependent ubiquitylation of DUSP4. DUSP4 promotes polyploidy during megakaryocyte differentiation. Thus PRMT1 caused profound epigenetic changes to promote leukemogenesis. In this vein, we established mouse AMKL models by bone marrow transplantation of 6133 cells as well as human AMKL patient samples respectively. Using this mouse model, we tested PRMT1 inhibitors, acetyltransferase inhibitors as well as other metabolic inhibitors. Treating cells with PRMT1 inhibitors as well as metabolic inhibitors promote MK differentiation of AMKL leukemia cells. Metabolomics analysis of cells recovered from mouse models will be discussed in the presentation. In summary, our data demonstrated that PRMT1 is a major sensor for metabolic stress and that PRMT1 in turn reprograms metabolic pathways to bring epigenetic changes in leukemogenesis. Therefore, targeting PRMT1 and downstream PRMT1-regulated metabolic pathways will offer new avenues in treating acute megakaryocytic leukemia and other hematological malignancies with defective megakaryocyte differentiation. Disclosures No relevant conflicts of interest to declare.

scholarly journals PERK participates in cardiac valve development via fatty acid oxidation and endocardial-mesenchymal transformation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takashi Shimizu ◽  
Kazuaki Maruyama ◽  
Takeshi Kawamura ◽  
Yoshihiro Urade ◽  
Youichiro Wada
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Umbilical Vein ◽  
Conditional Knockout ◽  
Cardiac Valve ◽  
Acid Oxidation ◽  
Loss Of Function ◽  
Mesenchymal Transformation ◽  
Valve Formation

AbstractProtein kinase R-like endoplasmic reticulum kinase (PERK) is one of the endoplasmic reticulum (ER) stress sensors. PERK loss-of-function mutations are known to cause Wolcott–Rallison syndrome. This disease is characterized by early-onset diabetes mellitus, skeletal dysplasia, and cardiac valve malformation. To understand the role of PERK in valve formation in vivo, we used an endothelial-specific PERK conditional knockout mice as well as in vitro PERK inhibition assays. We used ProteoStat dyes to visualize the accumulation of misfolded proteins in the endocardial cushion and valve mesenchymal cells (VMCs). Then, VMCs were isolated from E12.5 fetal mice, by fluorescence assisted cell sorting. Proteomic analysis of PERK-deleted VMCs identified the suppression of proteins related to fatty acid oxidation (FAO), especially carnitine palmitoyltransferase II (CPT2). CPT2 is a critical regulator of endocardial-mesenchymal transformation (EndoMT); however how TGF-β downstream signaling controls CPT2 expression remains unclear. Here, we showed that PERK inhibition suppressed, not only EndoMT but also CPT2 protein expression in human umbilical vein endothelial cells (HUVECs) under TGF-β1 stimulation. As a result, PERK inhibition suppressed mitochondrial metabolic activity. Taken together, these results demonstrate that PERK signaling is required for cardiac valve formation via FAO and EndoMT.

scholarly journals Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation

2018 ◽  
Vol 69 (3) ◽  
pp. 480-492.e7 ◽  
Author(s):  
Xiao-xue Li ◽  
Zhi-jing Wang ◽  
Yu Zheng ◽  
Yun-feng Guan ◽  
Peng-bo Yang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cell Survival ◽  
Fatty Acid Oxidation ◽  
Nuclear Receptor ◽  
Melanoma Cell ◽  
Metabolic Stress ◽  
Acid Oxidation

scholarly journals Carbohydrate-response Element-binding Protein Deletion Alters Substrate Utilization Producing an Energy-deficient Liver

2007 ◽  
Vol 283 (3) ◽  
pp. 1670-1678 ◽  
Author(s):  
Shawn C. Burgess ◽  
Katsumi Iizuka ◽  
Nam Ho Jeoung ◽  
Robert A. Harris ◽  
Yoshihiro Kashiwaya ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Pyruvate Dehydrogenase ◽  
Binding Protein ◽  
Pyruvate Dehydrogenase Complex ◽  
Substrate Utilization ◽  
Acid Oxidation ◽  
Nadh Ratio ◽  
Element Binding Protein ◽  
Dehydrogenase Complex

Livers from mice lacking the carbohydrate-responsive element-binding protein (ChREBP) were compared with wild type (WT) mice to determine the effect of this transcription factor on hepatic energy metabolism. The pyruvate dehydrogenase complex was considerably more active in ChREBP-/- mice because of diminished pyruvate dehydrogenase kinase activity. Greater pyruvate dehydrogenase complex activity caused a stimulation of lactate and pyruvate oxidation, and it significantly impaired fatty acid oxidation in perfused livers from ChREBP-/- mice. This shift in mitochondrial substrate utilization led to a 3-fold reduction of the free cytosolic [NAD+]/[NADH] ratio, a 1.7-fold increase in the free mitochondrial [NAD+]/[NADH] ratio, and a 2-fold decrease in the free cytosolic [ATP]/[ADP][Pi] ratio in the ChREBP-/- liver compared with control. Hepatic pyruvate carboxylase flux was impaired with ChREBP deletion secondary to decreased fatty acid oxidation, increased pyruvate oxidation, and limited pyruvate availability because of reduced activity of liver pyruvate kinase and malic enzyme, which replenish pyruvate via glycolysis and pyruvate cycling. Overall, the shift from fat utilization to pyruvate and lactate utilization resulted in a decrease in the energy of ATP hydrolysis and a hypo-energetic state in the livers of ChREBP-/- mice.

Sign in / Sign up

Export Citation Format

Share Document