Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonalcoholic steatohepatitis (NASH) is a progressive disease and poses a high risk of severe liver damage. However, the pathogenesis of NASH is still unclear. Accumulation of lipid droplets and insulin resistance is the hallmark of NASH. Pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) plays key role in glucose metabolism via regulating the activity of pyruvate dehydrogenase complex (PDC). Here, we demonstrated a novel of PDK4 in NASH by regulating hepatic steatosis and insulin signaling pathway in methionine and choline deficient (MCD) diet induced NASH model. Hepatic PDK4 levels were highly induced in human patients with NASH and MCD diet fed mice, as well as in hepatocytes treated with oleic acid. The glucose and lipid metabolism were impaired in Pdk4-/- mice. Pdk4 deficiency ameliorated the hepatic steatosis significantly in NASH mice. Pdk4-/--MCD mice had reduced liver weights and triglyceride (TG) levels. And Pdk4 deficiency dramatically reduced the expression of genes related to fatty acid uptake, synthesis and gluconeogenesis. In addition, elevated phosphorylated AMPK (p-AMPK), p-SAPK/JNK and diminished p-ERK, p-P38, p-Akt and p-mTOR/p-4EBP1 proteins were observed. In conclusion, our data indicated that PDK4 potentially contributes to the hepatic steatosis in NASH via regulating several signaling pathway and PDK4 may be a new therapeutic strategy against NAFLD.
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PMID:Pyruvate dehydrogenase kinase 4 mediates lipogenesis and contributes to the pathogenesis of nonalcoholic steatohepatitis. 2912 53

Mitochondria supply ~90% of the ATP required for contractile function in cardiac cells. While adult cardiomyocytes preferentially utilize fatty acids as a fuel source for oxidative phosphorylation, cardiac mitochondria can switch to other substrates when required. This change is driven in part by a combination of extracellular and intracellular signal transduction pathways that alter mitochondrial gene expression and enzymatic activity. The mechanisms by which extracellular metabolic information is conveyed to cardiac mitochondria are not currently well defined. Recent work has shown that adropin - a liver-secreted peptide hormone - can induce changes in mitochondrial fuel substrate utilization in skeletal muscle, leading to increased glucose use. In this study, we examined whether adropin could regulate mitochondrial glucose utilization pathways in cardiac cells. We show that stimulation of cultured cardiac cells with adropin leads to decreased expression of the pyruvate dehydrogenase (PDH) negative regulator PDK4, which reduces inhibitory PDH phosphorylation. The downregulation of PDK4 expression by adropin is lost when GPR19 - a putative adropin receptor - is genetically depleted in H9c2 cells. Loss of GRP19 expression alone increased PDK4 expression, leading to a reduction in mitochondrial respiration. Finally, we show that adropin-mediated GPR19 signaling relies on the p44/42 MAPK pathway, and that pharmacological disruption of this pathway blocks the effects of adropin on PDK4 in cardiac cells. These findings suggest that adropin may be a key regulator of fuel substrate utilization in the heart, and implicates an orphan G-protein coupled receptor in a novel signaling pathway controlling mitochondrial fuel metabolism.
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PMID:Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway. 2990 17


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