title: Inflammation increases pyruvate dehydrogenase kinase 4 (PDK4) expression via the Jun N-Terminal Kinase (JNK) pathway in C2C12 cells.
abstract: Chronic inflammation augments the deleterious effects of several diseases, particularly diabetes, cancer, and sepsis. It is also involved in the process of metabolic shift from glucose oxidation to lactate production. Although several studies suggest that the change in activity of the pyruvate dehydrogenase complex (PDC) is a major factor causing this metabolic change, the exact mechanism of the inflammatory state remains unclear. In this study, we investigated the effect of lipopolysaccharide (LPS) on the expression of pyruvate dehydrogenase kinase 4 (PDK4), which is strongly associated with inactivation of the PDC in C2C12 myoblasts. In C2C12 myoblasts, LPS exposure led to increased PDK4 mRNA and protein expression levels as well as lactate production in culture medium. However, the expression levels of other PDK isoenzymes (PDK1 - 3) remained unchanged. Additionally, we observed that LPS treatment induced phosphorylation of Jun N-Terminal Kinases (JNK). To confirm the role of JNK, we inhibited the JNK pathway and observed that PDK4 expression and lactate production were decreased, but p38 and ERK were not significantly changed. Taken together, our results suggest that LPS induces PDK4 expression and alters glucose metabolism via the JNK pathway.
authors.affiliation: Department of Biomedical Sciences, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Pharmaceutical Science and Technology, Catholic University of Daegu, Gyeongsan, Republic of Korea. Electronic address: syjeoung@cu.ac.kr.
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Jeoung
mesh_terms: D000818:Animals; D002460:Cell Line; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology*; D009220:Myositis / Q000139:chemically induced / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; C000631433:Pdk1 protein, mouse; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4
keywords: Diabetes; Glucose metabolism; Lipopolysaccharide (LPS); Mitogen-activated protein kinase (MAPK); Pyruvate dehydrogenase kinase 4 (PDK4); Sepsis