ABSTRACT
Adipose tissue (AT) is the primary reservoir of lipid, the major thermogenesis organ during cold exposure, and an important site for lactate production. However, the utilization of lactate as a metabolic substrate by adipocytes, as well as its potential involvement in the regulation of adipocyte thermogenesis, remain unappreciated. In vitro experiments using primary stromal vascular fraction preadipocytes isolated from mouse inguinal white adipose tissue (iWAT) revealed that lactate dehydrogenase B (LDHB), the key glycolytic enzyme that catalyzes the conversion of lactate to pyruvate, is upregulated during adipocyte differentiation, downregulated upon chronic cold stimulation, and regained after prolonged cold exposure. In addition, the global knockout of Ldhb significantly reduced the masses of iWAT and epididymal WAT (eWAT) and impeded the utilization of iWAT during cold exposure. In addition, Ldhb loss of function impaired the mitochondrial function of iWAT under cold conditions. Together, these findings uncover the involvement of LDHB in adipocyte differentiation and thermogenesis.
Subject(s)
Adipocytes, Beige , Animals , Mice , Adipocytes, Beige/metabolism , Lactic Acid/metabolism , Adipose Tissue , Adipose Tissue, White/metabolism , Thermogenesis , Mice, Inbred C57BL , Adipose Tissue, Brown/metabolismABSTRACT
@#Increased glycolysis is a major feature of metabolic reprogramming in cancer.Glycolysis provides not only energy for cancer cells but also necessary precursors for biosynthesis, which is important for promoting tumor growth.Cancer cells meet their own needs by regulating glycolytic enzymes, which play an active role in promoting cancer survival, metastasis, and invasion.Lactate dehydrogenase (LDH), as a key enzyme in glycolysis, consists of two subunits: lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB).LDHA is known to play a key role in aerobic glycolysis and has been extensively studied, whereas less has been done on LDHB.However, at present, more and more reports have revealed the important effects of LDHB on the progression of various cancers.A large number of studies have shown that LDHB is abnormally expressed in a variety of cancers, which is related to the malignant progression of tumors.The article reviews the research progress of LDHB in recent ten years, including its regulatory mechanism in tumor, its relationship with cancer development and its role as a biomarker in clinical diagnosis of cancer, which provides some insight for further investigation of the mechanism of LDHB in cancer research.
ABSTRACT
Acute myeloid leukaemia (AML) remains a therapeutic challenge and improvements in chemotherapy are needed. 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been proven to show superior anticancer effect compared with ATRA on various cancers. However, its potential effect on AML remains largely unknown. Lactate dehydrogenase B (LDHB) is the key glycolytic enzyme that catalyses the interconversion between pyruvate and lactate. Currently, little is known about the role of LDHB in AML. In this study, we found that ATPR showed antileukaemic effects with RARα dependent in AML cells. LDHB was aberrantly overexpressed in human AML peripheral blood mononuclear cell (PBMC) and AML cell lines. A lentiviral vector expressing LDHB-targeting shRNA was constructed to generate a stable AML cells with low expression of LDHB. The effect of LDHB knockdown on differentiation and cycle arrest of AML cells was assessed in vitro and vivo, including involvement of Raf/MEK/ERK signalling. Finally, these data suggested that ATPR showed antileukaemic effects by RARα/LDHB/ ERK-glycolysis signalling axis. Further studies should focus on the underlying leukaemia-promoting mechanisms and investigate LDHB as a therapeutic target.
Subject(s)
Cell Cycle Checkpoints/drug effects , Cell Differentiation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Glycolysis , L-Lactate Dehydrogenase/metabolism , Leukemia, Myeloid, Acute/pathology , Retinoic Acid Receptor alpha/metabolism , Retinoids/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Gene Expression Regulation, Leukemic/drug effects , Glycolysis/drug effects , Humans , Isoenzymes/metabolism , Leukemia, Myeloid, Acute/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Signal Transduction , raf Kinases/metabolismABSTRACT
Tumor cells possess a high metabolic plasticity, which drives them to switch on the anaerobic glycolysis and lactate production when challenged by hypoxia. Among the enzymes mediating this plasticity through bidirectional conversion of pyruvate and lactate, the lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB), are indicated. LDHA has a higher affinity for pyruvate, preferentially converting pyruvate to lactate, and NADH to NAD+ in anaerobic conditions, whereas LDHB possess a higher affinity for lactate, preferentially converting lactate to pyruvate, and NAD+ to NADH, when oxygen is abundant. Apart from the undisputed role of LDHA and LDHB in tumor cell metabolism and adaptation to unfavorable environmental or cellular conditions, these enzymes participate in the regulation of cell death. This review presents the latest progress made in this area on the roles of LDHA and LDHB in apoptosis and autophagy of tumor cells. Several examples of how LDHA and LDHB impact on these processes, as well as possible molecular mechanisms, will be discussed in this article. The information included in this review points to the legitimacy of modulating LDHA and/or LDHB to target tumor cells in the context of human and veterinary medicine.